Cell Biology

Research Description

Our lab focuses on three major areas of research:

Role of proteins involved in cellular and systemic metabolism

TTP is a protein that binds to AU-rich regions in the 3’ UTR of mRNA molecules and causes their degradation. It has been studied extensively in the field of inflammation. We recently showed that it also plays a role in cellular iron conservation. We have also shown that TTP is a key mediator of cellular metabolic processes. Our studies have demonstrated that TTP regulates glucose, fatty acid and branched-chain amino acid metabolism in the liver and muscle tissue. We also have evidence that TTP directly regulates mitochondrial electron transport chain (ETC) by targeting specific proteins in the ETC complexes. Finally, recent studies demonstrated that TTP also regulates systemic metabolism by targeting FGF-21 expression. We have both TTP Floxed mice (for the generation of tissue specific TTP knockout mice) and TTP knockout mice in the background of TNF-alpha receptor 1/2 knockout mice (to reduce the inflammatory burden).  Current studies include: 1) role of TTP in liver metabolism of fatty acids and glucose, 2) effects of TTP on mitochondrial proteins, 3) mechanism of TTP regulation of branched-chain amino acid levels and 4) role of TTP in cardiac metabolism.

Cardiac regeneration

Adult cardiomyocytes regenerate at a very low rate, but neonatal cardiomyocytes grow and replicate at a high rate. We have identified specific tandem zinc-finger (TZF) proteins that bind to mRNAs to regulate cardiac regeneration and cardiac development. Our studies suggest that these proteins may alter DNA repair in response to damage by regulating p53 and helicases. Current projects include: 1) identifying the mechanism by which TZF proteins regulate p53 and DNA damage, 2) characterization of the role of helicases in cellular proliferation and regeneration and 3) role of TZF proteins in cardiac development.

Characterization of cellular and mitochondrial iron regulation

Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), which plays a role in mitochondrial iron homeostasis and mitochondrial iron export. Mice with ABCB8 knocked out in the heart develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have shown that a pathway involving mTOR and tristetraprolin, treatment with doxorubicin (an anticancer drug that also causes cardiomyopathy) and SIRT2 protein also impact cellular and/or mitochondrial iron regulation. Current studies in this area include: 1) further characterization of ABCB8 in iron homeostasis in other organs and disorders, 2) characterization of the mechanism for iron regulation by SIRT2, 3) identification of the mechanism by which mTOR is regulated by iron, 4) role of iron in viral infection, particularly HIV, 5) characterization of the effects of iron on mitochondrial dynamics and 6) identification of novel mitochondrial-specific iron chelators.

For more information, see Dr. Ardehali's faculty profile.

Publications

See Dr. Ardehali's publications in PubMed.

Contact

Dr. Ardehali

Research Description

Topic 1. Mechanisms underlying dopamine neurogenesis
The floor plate, the ventral organizing center in the embryonic neural tube, patterns the neural tube by secreting the potent morphogen Shh. Using genetic fate mapping, we have recently shown that the midbrain floor plate, unlike the hindbrain and spinal cord floor plate, is neurogenic and is the source of midbrain dopamine neurons (Joksimovic, et al, 2009 Nature Neuroscience, Joksimovic et al. 2009 PNAS). We are interested in understanding pathways that are involved in floor plate neurogenesis and production of dopamine neurons. We have shown that Wnt signaling is critical for the establishment of the dopamine progenitor pool and that miRNAs may modulate the dosage and timing of the Wnt pathway (Anderegg et al, PloS Genetics 2013).

Topic 2. Deconstructing Dopaminergic Diversity
The neurotransmitter dopamine, produced mainly by midbrain dopaminergic neurons, influences a spectrum of behaviors including motor, learning, reward, motivation and cognition. In accordance with its diverse functions, dopaminergic dysfunction is implicated in a range of disorders affecting millions of people, including Parkinson’s disease (PD), schizophrenia, addiction and depression. How a small group of neurons underpins a gamut of key behaviors and diseases remains enigmatic. We postulated that there must exist several molecularly distinct dopaminergic neuron populations that, in part, can account for the plethora of dopaminergic functions and disorders. We are currently working to test this hypothesis and define dopamine neuron subtypes.

Topic 3. MicroRNAs in Schwann cell (SC) differentiation
MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes including differentiation, proliferation and cancer. We have studied the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzyme, Dicer1 (Yun et al, 2010, J Neurosci) . We reveal that mice lacking Dicer1 in SC (Dicer1 cKO) display a severe neurological phenotype resembling congenital hypomyelination. SC lacking Dicer1 are stalled in differentiation at the promyelinating state and fail to myelinate axons. We are beginning to determine the molecular basis of this phenotype. Understanding this will be important not only for congenital hypomyelination, but also for peripheral nerve regeneration and SC cancers.

For more information, please see Dr. Awatramani's faculty profile.

Publications

View Dr. Awatramani's complete list of publications in PubMed.

Contact Us

Rajeshwar Awatramani, PhD at 312-503-0690

Research Description

The research in my lab is centered on the “espins,” a novel family of actin-bundling proteins and the elucidation of their roles in the stereocilia of sensory hair cells in the inner ear. Espins are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle scaffold at the core of hair cell stereocilia and are the target of deafness mutations in mice and humans.

For lab information and more, please see Dr. Bartles’ faculty profile.

Publications

See Dr. Bartles' publications on PubMed.

Contact

Contact Dr. Bartles at 312-503-1545.

Lab Staff

Postdoctoral Fellow

Lili Zheng

Research Description

An epidemic of obesity and diabetes has continued to sweep through the industrialized world, already posing a risk to over one-third of the US population who are overweight or obese. Although both physical inactivity and overnutrition are tied to “diabesity,” recent evidence indicates that disruption of internal circadian clocks and sleep also play a role. The primary research focus in our laboratory is to apply genetic and biochemical approaches to understand the basic mechanisms through which the circadian clock regulates organismal metabolism. We anticipate that a better understanding of clock processes will lead to innovative therapeutics for a spectrum of diseases including diabetes, obesity, autoimmunity and cancer. 

Studies of Clock Function in Beta Cell Failure and Metabolic Disease

Glucose homeostasis is a dynamic process subject to rhythmic variation throughout the day and night. Impaired glucose regulation leads to metabolic syndrome and diabetes mellitus, disorders that are also associated with sleep-wake disruption, although the molecular underpinnings of circadian glucose regulation have been unknown. Work from our laboratory first demonstrated an essential role of the intrinsic pancreatic clock in insulin secretion and diabetes mellitus and present efforts focus on dissecting the genomic and cell biologic link between clock function and beta cell failure (Nature, 2010, 2013). 

Studies of Clock Regulation of Metabolic Epigenetics

In 2009 we first reported discovery that the circadian system plays a central role in metabolism through regulation of NAD⁺ biosynthesis (Science, 2009). NAD⁺ is a precursor of NADP⁺ and is required for macromolecule biosynthesis, in addition to functioning as an oxidoreductase carrier.  NAD⁺ is also a required cofactor for the class III histone deacetylases (silencer of information regulators, SIRTs), nutrient-responsive epigenetic regulators  Biochemical analyses show that SIRT1 deacetylates substrate proteins generating O-acetyl-ADP-ribose and nicotinamide, which is then regenerated to NAD⁺ by the enzyme nicotinamide phosphoribosyl transferase (NAMPT). We originally showed that CLOCK/BMAL1 directly control the transcription of Nampt and in turn control the activity of SIRT1—identifying a feedback loop composed of CLOCK/BMAL1-NAMPT/SIRT1. More recently, we have identified a role for the clock-NAD⁺ pathway in mitochondrial respiration (Science, 2013), and our present efforts include the analysis of clock-NAD⁺ regulation of cellular redox and epigenetic regulation, with the ultimate aim of applying such knowledge to studies of cell growth and stress response.

For more information, please see Dr. Bass' faculty profile or lab website.

Publications

See Dr. Bass' publications in PubMed.

Contact Info

Dr. Bass

Research Description

Dr. Batlle’s lab currently focuses on the renin angiotensin system as it relates to the understanding of this system in rodent kidney physiology. Of particular focus are the pathways and mechanisms that determine the enzymatic cleavage and degradation of Angiotensin II and other peptides within the system by ACE2-dependent and independent pathways. The lab uses a holistic approach involving ex vivo, in vitro and in vivo studies using various rodent models of diabetic and hypertensive kidney disease.

The lab is also involved in the search for biomarkers of kidney disease progression as part of the NIDDK Consortium on CKD. Other areas of research interest include nocturnal hypertension and the physiology and pathophysiology of electrolyte disorders such as distal renal tubular acidosis.

For more information, please see Dr. Batlle's faculty profile.

Publications

See Dr. Batlle's publications in PubMed.

Contact

Dr. Batlle

Our primary research interests are in eosinophil- and mast cell-associated diseases, including asthma, hypereosinophilic syndromes and systemic mastocytosis. We have a particular interest and focus on understanding the function of Siglec-8, an inhibitory and sometimes pro-apoptotic receptor expressed on human eosinophils, basophils and mast cells and how it can be targeted for clinical benefit. Animal models are used to study its closest counterparts, such as Siglec-F. In studies involving carbohydrate biochemistry and glycoproteomics, the lab is isolating and characterizing potential glycan ligands for Siglec-F and Siglec-8. Finally, we are interested in food allergy and anaphylaxis and are exploring new ways to prevent allergic reactions in vitro and in vivo. 

Publications

View lab publications via PubMed. 

For more information, please see Dr. Bochner's faculty profile or view more information regarding our NHLBI-funded work.

Contact Us

Email Dr. Bochner
Phone 312-503-0068 or the Bochner Lab at 312-503-1396.

Lab Staff

Melanie C. Dispenza, MD, PhD
Postdoctoral Fellow
312-503-0066

Piper Robida, PhD
Postdoctoral Fellow
312-503-0066

Krishan Chhiba, BS
MD/PhD Candidate
312-503-8032

Yun Cao, MS
Research Lab Manager 1
312-503-1396

Rebecca Krier, MS
Research Lab Manager 1
312-503-8032

Jeremy O’Sullivan, PhD
Research Assistant Professor
312-503-0066

Soon Cheon Shin, PhD
Research Associate
312-503-1131

Research Description

The current projects in Dr. Budunova’s lab are centered on the role of the glucocorticoid receptor (GR) as a tumor suppressor gene in skin. We showed that skin-specific GR transgenic animals are resistant to skin carcinogenesis and GR KO animals are more sensitive to skin tumor development.  We are also interested in the role of GR in the maintenance of skin stem cells (SC). We found that GR/glucocorticoids inhibit the expression of numerous SC markers in skin including CD34- a marker of hair follicular epithelial SC and reduce the proliferative potential of skin SCs.

The glucocorticoids remain among the most effective and frequently used anti-inflammatory drugs in dermatology. Unfortunately, patients chronically treated with topical glucocorticoids, develop side effects including cutaneous atrophy. GR controls gene expression via (i) transactivation that requires GR dimerization and binding as homo-dimer to gene promoters and (ii) transrepression that is chiefly mediated via negative interaction between GR and other transcription factors including pro-inflammatory factor NF-kB. In general, GR transrepression is the leading mechanism of glucocorticoid anti-inflammatory effects, while many adverse effects of glucocorticoids are driven by GR transactivation.

Our laboratory has been involved in delineation of mechanisms underlying side effects of glucocorticoids in skin. Using GRdim knockin mice characterized by impaired GR dimerization and activation, we found that GR transactivation plays an important role in skin atrophy. These data suggested that non-steroidal selective GR activators (SEGRA) that do not support GR dimerization, could preserve therapeutic potential of classical glucocorticoids but have reduced adverse effects in skin.  We are testing effects of the novel SEGRA called Compound A– a synthetic analog of natural aziridine precursor from African bush Salsola Botch in skin. We have also established anti-cancer GR-dependent activity of Compound A in epithelial and lymphoma cells.

Using knockout mice for the major GR target genes including Fkbp5 (GR chaperone) and DDIT4/REDD1 (one of the major negative regulators  of mTORC), we discovered that blockage of Fkbp5 and REDD1 significantly changes GR function and greatly protects skin against glucocorticoid-induced atrophy. This suggests a novel GR-targeted anti-inflammatory therapy where glucocorticoids are combined with inhibitors of GR target genes.

For more information, please see Dr. Budunova’s faculty profile.

Publications

See Dr. Budunova's publications in PubMed.

Contact Budunova Lab

Contact the Budunova Lab at 312-503-4669 or visit in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-015, Chicago, IL 60611

Faculty

Irina Budunova, MD, PhD

Research Associates

Pankaj Bhalla, PhD, Gleb Baida, PhD, Anna Klopot, PhD

Research Description

We are focused on a group of neurodegenerative diseases collectively known as synucleinopathies, characterized by the aggregation of α-synuclein (α-syn). These include Parkinson's Disease, Dementia with Lewy bodies and Multiple Systems Atrophy among others. We use diverse systems that span from yeast to mammalian models to study these diseases. In particular, we are interested in the role Ca²⁺ signaling plays in the toxicity caused by α-syn and to delineate basic mechanisms of Ca²⁺ signaling relevant to neuronal physiology.

For more information, see Dr. Caraveo Piso's faculty profile.

Publications

Please see Dr. Caraveo Piso's publications on PubMed.

Contact Information

Gabriela Caraveo Piso, PhD

Assistant Professor in Neurology

Ward 10-150

312-503-4492

Research Description

The Chakravarti laboratory is interested in understanding the roles of nuclear hormone signaling and epigenetic modifications in regulating normal cell and organ physiology and how altered transcriptional and epigenetic signaling contributes to cancer development and metastasis.  To pursue these overall goals, we are currently focusing on three research areas which are of significant current interests in biomedical field.

Research Area 1: Transcriptional Regulation of Tumor Development: Cancer is a complex disease and remains poorly understood. In particular, how altered transcriptional and epigenetic regulation contributes to cancer development and progression is not clear. We have recently discovered and characterized a new family of proteins termed the THAP family. Using xenograft mouse model, next generation mRNA and ChIP deep sequencing, extensive analysis of human progressive cancer tissue samples and state-of-the-art molecular techniques, members of the laboratory are determining the role of this novel THAP domain transcription factor and its cofactor HCF1 in cell cycle regulation and cancer progression. These studies should advance our knowledge of cancer progression and may provide a molecular target for therapeutic intervention.  

Research Area 2: Nuclear Hormone Receptor Signaling in Physiology and Uterine Fibrosis: Alterations of receptor/hormone function and coactivator and corepressor proteins have been implicated in several human diseases including cancer and fibrotic diseases.  We are currently determining the role of epigenetic changes and novel cofactors in hormone signaling and prostate and breast cancer. Tissue fibrosis is a major health problem in the world. We have profiled all 48 human nuclear receptors in uterine fibroids and found profound changes of receptor expression in normal and fibroid uterine tissues.  Laboratory members are currently using biochemical, bioinformatics, ChIP, deep sequencing and molecular techniques to determine epigenetic cross talk in hormone signaling and human cancer and uterine fibroids. 

Research Area 3: Epigenetic Modifications and Effectors of Chromatin Function: Combinatorial histone modifications including acetylation, methylation and phosphorylation play important regulatory roles in gene expression, chromatin function and cell cycle progression. We have recently demonstrated that the SR-proteins are critical cell cycle-dependent effector proteins for histone H3 serine 10 phosphorylation. We are also determining the role of histone H3 T11 phosphorylation and its effector protein WDR5 in androgen receptor function and in prostate cancer. Members in the laboratory are currently investigating the mechanisms by which these “effector-modification” interactions contribute to cell cycle progression and human diseases including cancer.

For more information, please see, visit the Dr. Chakravarti's faculty profile.

Publications

See Dr. Chakravarti's publications in PubMed.
Editorial Board:  Molecular Endocrinology 2011- present, Mol. Cell. Biol. 2014-2017
The Editor of a Book volume on “Regulatory Mechanisms in Transcriptional Signaling” in Progress in Molecular Biology and Translational Science (Vol 87), published in Aug 2009, Academic Press, Chakravarti, D. Editor

Staff Listing

Post-doctoral Fellows

J. Brandon Parker, Ph.D
Ji-Young Kim, Ph.D

Graduate Students

Aurimas Vinckevicius
Hanwei Yin
Mthabisi Moyo

Research Assistant

Sanjay Kottapalli

Contact Us

Dr. Chakravarti

Contact Chakravarti lab at 312-503-0782, 312-503-0783 or 312-503-0784. Our fax is 312-503-0095.

Historically, reactive oxygen species (ROS) have been thought to be cellular damaging agents, lacking a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer and premature aging. This guilt by association relationship left a picture of ROS as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution. It appears that oxidative metabolism is no different. More and more evidence suggests that low levels of ROS are critical for healthy cellular function. This idea was first proposed in the mid-1990s when low levels of hydrogen peroxide (H2O2) were demonstrated to be important for cellular signaling. Although mitochondria were known to produce H2O2, NADPH oxidases (NOXs) were the subject of early study due to their well-described role as ‘dedicated H2O2 producers’ in phagocytes. We provided early evidence in the late 1990s that mitochondria release H2O2 to regulate the transcription factor hypoxia inducible factor 1 (HIF-1) (i.e. oxygen sensing). Subsequently, we showed that mitochondrial release of H2O2 can activate p53 and NF-κB. We have recently demonstrated that mitochondria-generated H2O2 can regulate other physiological processes including stem cell differentiation, adaptive immunity and replicative life span of mammalian cells. Furthermore, we have shown that cancer cells co-opt mitochondria-generated H2O2 to hyper-activate signaling resulting in tumor cell proliferation. There have been numerous reports from other laboratories in the past decade also highlighting the importance of mitochondrial H2O2-dependent signaling in metabolic adaptation, immunity, differentiation, autophagy and organismal longevity. We propose that mitochondrial release of H2O2 has evolved as a method of communication between mitochondrial function and other cellular processes to maintain homeostasis and promote adaptation to stress.

Publications

See Dr. Chandel's publications in PubMed.

For more information, please see Dr. Chandel's faculty profile or visit the Chandel Lab website.

Contact Us

Contact Dr. Chandel’s Lab at 312-503-1792

Lab Staff

Lauren Diebold
Graduate Student

James Eisenbart
Lab Manager

Manan Mehta
Graduate Student

Colleen Reczek, PhD

Inma Reyes, PhD

Arianne Rodriguez
Graduate Student

Sam Weinberg
Graduate Student

Research Description

      Integrated genomic analysis by TCGA revealed tat GBMs can be classified into four clinically relevant subtypes, proneural (PN), neural, mesenchymal (Mes) and classical GBMs with each characterized by distinct gene expression signatures and genetic alterations. We reported that PN and Mes glioma stem cells (GSCs) subtypes also have distinct dysregulated signaling pathways. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, invasion/metastasis, angiogenesis and therapy responses of GSCs and GBMs.

1. MicroRNAs (miRs) and non-coding RNAs in GSCs and GBMs – miRs and other small non-coding RNAs act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms.  Dysregulated miRs/noncoding RNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of miRs influence GBM malignant phenotypes through interaction with signaling pathways, that in turn, influence proneural (PN)- and mesenchymal (Mes)-associated gene expression in GSCs and GBM phenotypes. We study the molecular consequences and explore clinical applications of modulating miRs and signaling pathways in GBMs.  We are establishing profiles of non-coding RNAs in these GSCs and study mechanisms and biological influences of these non-coding RNAs in regulating GSC biology and GBM phenotypes. In addition, we explore novel therapeutic approaches of delivery of tumor suppressive miRs into GSC brain xenografts in animals.

2.  Autophagy in GBMs. (Macro)autophagy is an evolutionally conserved dynamic process whereby cells catabolize damaged proteins and organelles in a lysosome-dependent manner. Autophagy principally serves as an adaptive role to protect cells and tissues, including those associated with cancer. Autophagy in response to multiple stresses including therapeutic treatments such as radiation and chemotherapies provides a mechanism for tumor cell to survive and acquire resistance to therapies. Tumors can use autophagy to support and sustain their proliferation, survival, metabolism, invasiveness, metastasis and resistance to therapy. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes on autophagy proteins inhibits autophagy and enhances the efficacy of combination therapies for GBMs. We examine whether cross-talks between miRs, autophagy and oncogenic signaling pathways regulate GSC stemness and phenotypes.

3. Heterogeneity, epigenetic regulation, DNA damage and metabolic pathways in GSCs and GBMs. Intratumoral heterogeneity is a characteristic of GBMs and most of cancers. Phenotypic and functional heterogeneity arise among GBM cells within the same tumor as a consequence of genetic change, environmental differences and reversible changes in cell properties. Subtype mosaicism within the same tumor and spontaneous conversion of human PN to Mes tumors have been observed in clinical GBMs. We explore an emerging epigenetic marker with distinct functions such as DNA methylation together with genetic mapping of these markers to assess their contributions to GBM heterogeneity. In addition, compared with PN GSCs, DNA damage and glycolytic pathways are aberrant active in Mes GSCs. We investigate the mechanisms by which these pathways regulate GSC and GBM phenotypes and responses to therapies.

4. Oncogenic receptor tyrosine kinase (RTKs) signaling, small Rho GTPase regulators in GBM and GSCs: Small Rho GTPases such as Rac1 and Cdc42 modulate cancer cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII and PDGFR alpha promote glioma growth and invasion by distinct mechanisms involving phosphorylation of Dock180, a Rac-specific guanidine nucleotide exchange factor (GEF) and DCBLD2, an orphan membrane receptor. We are currently investigating involvement of other modulators/GEFs and other Rho GTPases in modulating GSC and GBM phenotypes and responses to therapy.

For more information, please see Dr. Cheng's faculty profile and lab website.

Publications

View Dr. Cheng's complete list of publications in PubMed.

Contact Us

Shi-Yuan Cheng, PhD at 312-503-5314

Visit us on campus in the Lurie Building, Room 6-119, 303 E Superior Street, Chicago, Illinois 60611.

Research Description

Movement is a fundamental characteristic of life. Cell movement is critical for normal embryogenesis, tissue formation, wound healing and defense against infection. It is also an important factor in diseases such as cancer metastasis and birth defects. Movement of components within cells is necessary for mitosis, hormone secretion, phagocytosis and endocytosis. Molecular motors that move along microfilaments (myosin) and microtubules (dynein) power these movements. Our goal is to understand how these motors produce movement and are regulated. We wish to define their involvement in intracellular, cellular and tissue function and disease—with the long-term goal of developing therapies for the treatment of diseases caused by defects in these molecular motors.

Our work involves the manipulation of myosin and dynein function in the single celled eukaryote Dictyostelium, cultured mammalian cells and transgenic and knockout mice. Yeast two-hybrid screens to identify proteins that interact with or regulate myosin and dynein and characterization of gene expression are being used to define the pathways regulating myosin and dynein. To analyze the biological significance of myosin and dynein, we use confocal and digital microscopy of living cells, analysis of cell movement, vesicle transport and cell division. We employ biochemical techniques including heterologous expression, enzyme purification and characterization and analysis of how phosphorylation state affects physiological function. We are pursuing signal transduction studies to understand the physiologically important pathways that regulate cell motility and biophysical studies such as in vitro motility assays to understand how these molecular motors function at the molecular level.

For lab information and more, see Dr. Chisholm's faculty profile.

Publications

See Dr. Chisholm's publications on PubMed.

Contact

Contact Dr. Chisholm at 312-503-3209.

Research in the Crispino laboratory is focused on investigating the regulatory mechanisms governing normal and malignant blood cell development, with an emphasis on understanding the growth of erythroid cells (red blood cells) and megakaryocytes (platelet-producing cells). Major areas of focus include: 1) Understanding the link between Down syndrome and leukemia. We are investigating how mutations in GATA1, a key transcription factor that regulates megakaryocyte growth contribute to leukemia. We are also studying the mechanisms by which trisomy 21 promotes the development of leukemia with a long-term goal of unraveling the mystery of why children with DS are predisposed to leukemia. Our current efforts are focused on characterizing the contributions of two chromosome 21 genes: DYRK1A, a kinase and ERG, a transcription factor. 2) Development of novel therapeutics for human megakaryocytic malignancies. In collaboration with the Broad Institute, we identified several small molecules that induce proliferation arrest, polyploidization and maturation of malignant megakaryocytes. By a three-pronged target identification approach, we discovered that a key target of these small molecules is Aurora A Kinase. We are currently investigating the utility of AURKA inhibitors as potential new, targeted therapies for acute megakaryocytic leukemia. In addition, we have completed extensive pre-clinical studies to support the testing of AURKA inhibitors in a related blood disease named primary myelofibrosis, a subtype of the MPNs. 3) Investigating the mechanisms of red blood cell development. We are currently studying two aspects of red blood cell development. First, based on our previous discovery that the coalescence of cytoplasmic vesicles is required for enucleation of erythroblasts, we are probing the requirements for specific motor proteins in enucleation and identifying small molecules that enhance enucleation in culture. This research will aid in the development of new strategies to generate red blood cells for transfusion in vitro from stem cells. Second, in line with our expertise and significant interest in GATA1 biology, we are studying the effects of GATA1 mutations on erythropoiesis. We are using state of the art approaches to identify essential, direct GATA1 target genes whose expression depends on the presence of the full-length wild-type protein. This research is relevant to rare red blood cell disorders such as Diamond Blackfan Anemia. Overall, the lab seeks to make seminal basic science discoveries while simultaneously translating these discoveries in ways that will benefit patients with hematologic malignancies.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of John Crispino, PhD.

Contact Us

Contact Dr. Crispino at 312-503-1504 or the Crispino Lab at 312-503-1433.

Lab Staff

Gina Kirsammer, PhD
Research Assistant Professor
312-503-1433

Paul Lee, MD, PhD
Pediatric Hematology/Oncology Fellow
312-503-1433

Maureen McNulty
DGP Student
312-503-1433

Rachael Schultz
Research Technologist
312-503-1433

Monika Stankiewicz, PhD
Post-Doctoral Fellow
312-503-1433

Praveen Suraneni, PhD
Post-Doctoral Fellow
312-503-1433

Benjamin Thompson, MD/PhD
Post-Doctoral Fellow
312-503-0827

Qiang (Jeremy) Wen, MD/PhD
Research Assistant Professor
312-503-1434

Andrew Volk
Post-Doctoral Student
312-503-1434

Qiong Yang, MD/PhD
Visiting Scholar
312-503-1433

The folding of DNA within nuclei and chromosomes is one of the great mysteries of biology, impacts gene regulation and influences heredity. At the most basic level, DNA is wrapped around histones in the nucleosome to form an extended “beads-on-a-string” chromatin fiber. Chromosome conformation capture, involving chemical cross-linking of chromatin followed by restriction digestion, ligation and high-throughput DNA sequencing (Hi-C), detects further folding of the chromatin fiber. Hi-C has revealed “topologically associating domains” (TADs), regions of intra-chromosomal self-association that are interspersed with regions of little or no such self interaction, which are prevalent throughout metazoans. By applying Hi-C to the polytene chromosomes of Drosophila, I established that polytene bands are equivalent to TADs, connecting chromatin folding inferred from Hi-C with direct, physical observations from light microscopy. Furthermore, TADs are conserved between polytene and diploid cells identifying the polytene band-interband pattern as a general principle of interphase chromosome architecture.  Chromatin between TADs exists in a fully extended state, whereas TADs, which are up to 30-foldmore condensed, reflect the next higher level of stable chromosome folding.

Through experimental and computational improvements to the Hi-C method, I mapped chromatin interactions at sub-kilobase resolution, the highest resolution for a metazoan genome to-date.  This allowed me to determine the locations of chromatin loops across the Drosophila genome. Loops were frequently located within domains of polycomb-repressed chromatin. Loop boundaries or “anchors” were frequently associated with the protein Polycomb, a subunit of Polycomb Repressive Complex 1 (PRC1). Promoters located at PRC1 loop anchors regulate some of the most important developmental genes and are less likely to be expressed than those not at PRC1 loop anchors. Although DNA looping has most commonly been associated with enhancer–promoter communication, these results indicate that loops are also associated with gene repression.

These advances have significantly furthered our understanding of nuclear organization, but DNA folding at the scale of tens-of-nanometers and beyond is still largely undetermined. Enhancers, cis-regulatory regions often located a distance from gene promoters, are important for tissue specific gene expression and malfunction in cancer. Enhancers are often found within TADs and intra-TAD chromatin folding influences proper gene regulation by modulating enhancer-promoter interactions. Disrupting TAD structure pathogenically rewires these interactions in human disease, so determining how TADs fold is of great interest. At the highest level of DNA folding, mitotic chromosomes are one of the most recognizable structures in cell biology, yet a detailed understanding of their internal structure has remained elusive. Faithful propagation of mitotic chromosomes underlies cellular heredity, so it is important to relate chromatin folding within interphase TADs to chromosome condensation during metaphase. My lab combines concepts and approaches from structural biology with methods and analytical tools from molecular biology and genomics to determine the structural basis of chromatin condensation within TADs and mitotic chromosomes. A combination of molecular biology, biochemistry, genomics and imaging will pave the way for a deeper understanding of chromatin structure as well as unravel principles.

Visit the Eagen Lab Website.

For more information, visit the faculty profile page of Kyle Eagen

Publications

View lab publications via PubMed.

Contact

Email Dr. Eagen

Research Description

Our work focuses on the mechanisms underlying neurite degeneration and synapse loss in Alzheimer’s disease and related neurodegenerative disorders. We are interested in the relationship between beta-amyloid deposition and the progressive formation of dystrophic neurites and cell death in hippocampal neurons.

Recently, we have determined that the microtubule associated protein tau plays an essential role in beta-amyloid-induced neurite degeneration. These results constitute the first direct evidence of a mechanistic link between beta-amyloid deposition and tau in central neurons. Furthermore, our results indicated that beta-amyloid induces calpain-mediated tau cleavage leading to the generation of a 17 kDa neurotoxic fragment in hippocampal neurons both in culture model systems and in AD human brain samples. Currently, we are analyzing the mechanisms by which this tau fragment mediates beta-amyloid-induced neurite degeneration. These studies are being performed by means of a variety of cell and molecular biology techniques.

For lab information and more, see Dr. Ferreira's faculty profile and lab website.

Publications

See Dr. Ferreira's publications on PubMed.

Contact

Contact Dr. Ferreira at 312-503-8250.

Lab Staff

Technical Staff

Sana Afreen, Chloe Parker

Research Description

My research program is focused on the important basic question of how chromosomes are segregated during cell division to ensure the complete and accurate inheritance of the genome. Chromosome instability is a hallmark of cancer and can drive tumorigenesis. Therefore, how centromere specification is controlled is a basic biological question with great therapeutic potential. Centromeres are specified by the incorporation of a histone variant CENP-A in a centromere specific nucleosome. The stable inheritance of this locus is controlled by an epigenetic pathway and does not depend on the underlying DNA sequence. My research program is using a combination of cell biology, biochemical purification and in vitro reconstitution of centromeric chromatin to discover the mechanisms of epigenetic inheritance and CENP-A function during mitosis. A key to understanding the epigenetic inheritance of centromeres is determining the process by which new CENP-A nucleosomes are deposited. Our lab is studying how activity of the CENP-A chromatin assembly factor HJURP is coupled to existing centromeres. Non-coding RNAs, as well as chromatin modifying enzymes have been implicated in the process and we are exploring how these factors contribute to specific assembly of the CENP-A nucleosomes. We have identified novel post translational modifications of the CENP-A amino-terminus and we are working to determine how these modifications contribute to genomic stability and accurate chromosome segregation. Our immediate goal is to determine the mechanism of epigenetic centromere inheritance, with a long-term goal of delineating the role of this process in tumorigenesis so as to translate our basic understanding of the enzymes and proteins involved in this process into therapeutic approaches for genomic instability in cancer.

For lab information and more, see Dr. Foltz's faculty profile and lab website.

Publications

See Dr. Foltz's publications on PubMed.

Contact

Contact Dr. Foltz at 312-503-5684.

Research Description

One of the remarkable features of eukaryotic cells is their ability for rapid transport of intracellular organelles in the cytoplasm. Examples of such transport include segregation of chromosomes during cell division and the transport of organelles in neurons from the cell body into axons and dendrites. Movements of organelles are powered by molecular motors. Microtubule motors(kinesins and dyneins) move along microtubules and myosins move along microfilaments.

We use two cellular models to discover how multiple motors on the surface of the same cargo work together in organelle movement and how these motors are attached to the surface of organelles and what regulates their activity. One model is cultured pigment cells (melanophores). These cells activate movement of pigment organelles in response to hormone-modulated changes of cAMP concentration. The movement of pigment organelles is powered by three different motors (two microtubule motors of different polarity and a myosin) and this system is very convenient for analysis of motor regulation. A second model is cultured Drosophila cells that we use to individual components of transport machinery by using RNAi. In our work, we employ techniques of cell and molecular biology and computer-assisted microscopy of living cells and purified organelles as well as high-resolution and high-sensitivity biophysical methods.

For lab information and more, see Dr. Gelfand's faculty profile and lab website.

Publications

See Dr. Gelfand's publications on PubMed.

Contact

Contact Dr. Gelfand at 312-503-0530.

Lab Staff

Postdoctoral Fellows

Urko Del Castillo, Anna Gelfand, Wen Lu, Rosalind Norkett, Bhuvanasundar Ranganathan, Amelie Robert

Graduate Student

Yinlong Song

Technical Staff

Margot Lakonishok

Research Description

We focus on the structure and function of cytoskeletal systems, particularly the intermediate filament (IF) system in fibroblasts, epithelial cells and nerve cells. IFs are composed of large families of proteins that vary in composition from one cell type to another, even among cells in the same tissue. Using a variety of techniques, we have demonstrated that IFs form elaborate networks that course throughout the cytoplasm and establish connections with both the nuclear and cell surfaces.

At the nuclear surface, they are linked either directly or indirectly with the nuclear lamins, which are chromatin-associated IF protein family members. At the level of the plasma membrane, IFs are involved as cytoskeletal linkages to the focal adhesion of fibroblasts and the desmosomes and hemidesmosomes of epithelial cells. Throughout the cytoplasm, we have shown that IFs are associated with the other cytoskeletal elements, such as microtubules and microfilaments.

Our approach to studying the IF system involves biochemical, morphological, immunological, cell physiological and molecular techniques. Our hypothesis is that the IF system forms a continuous network linking the nuclear and cell surfaces, functioning in such diverse activities as the establishment and maintenance of cell shape, organelle movements within the cytoplasm, nuclear positioning, nuclear-cytoplasmic interactions and signal transduction.

Since many human diseases have been linked to changes in cytoskeletal IF systems, we are also developing models to study the mechanisms involved in IF alterations in various diseases. One example is amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) in which we have been able to induce neurofibrillary tangles to form in single cultured nerve cells. These tangles are similar to those found in ALS neurons. Therefore, we are able to study the effects of neurofilament tangle formation in single cells. During the summer, researchers from this laboratory also conduct studies on the mechanisms of chromatin/nuclear envelope interactions in eggs of the surf clam at the Marine Biological Laboratory in Woods Hole.

For lab information and more, see Dr. Goldman's faculty profile and lab website.

Publications

See Dr. Goldman's publications on PubMed.

Contact

Contact Dr. Goldman at 312-503-4215.

Lab Staff

Research Faculty

Heike Folsch, Edward Kuczmarski, Stuart Stock

Postdoctoral Fellows

Anne Goldman, Mark Kittisopikul, Suganya Sivagurunathan, Amir Vahabikashi

Technical Staff

Kyung Myung, Fiona Nicdao, Samuel Romo

The ability of individual cells to adhere and coalesce into distinct tissues is a major feature of multicellular organisms. Research in my laboratory centers on a protein complex that projects from the cell surface and forms a structural “Velcro” that holds cells to one another. This complex is comprised of a transmembrane “cadherin” component that mediates Ca++-dependent homophilic recognition and a number of associated “catenins” that link cadherins to the underlying cytoskeleton.  A major focus in our lab is to understand how these catenins direct static versus fluid adhesive states at the plasma membrane, as well as gene expression and differentiation in the nucleus. These basic questions are shedding new light on how dysregulation of the cadherin/catenin adhesion system drives pathologies such as asthma, fibrosis and cancer.

Publications

See Dr. Gottardi's publications in PubMed.

For more information, please see Dr. Gottardi's faculty profile.

Lab Staff

Annette Flozak
Research Technologist
312-503-0409

Megan Novak
Graduate Student- TGSG
312-503-0409

Stephen Sai Folmsbee
Graduate Student- MEDP TGSG
312-503-0409

Alex Yemelyanov
Research Assistant Professor
312-503-1918

Research Description

Dr. Green's research program focuses on how cell-cell adhesion molecules and their associated proteins integrate mechanical and chemical signaling pathways to contribute to the development and maintenance of multicellular tissues. In particular they are investigating how specialized intercellular junctions called desmosomes are assembled and function in ways that transcend their classic textbook definition as spot welds. The lab has shown that desmosomal cadherins help control the balance of proliferation and differentiation and even regulate the production of cytokines that participate in paracrine signaling. Loss of this “brake” results in increased allergic and inflammatory pathways that underlie pathogenesis in inherited disease and possibly cancer, including melanoma. Desmosomes also integrate the functions of other intercellular junctions including gap junctions and interfering mutations can cause lethal heart arrhythmias.

The lab uses a multi-faceted approach, including but not limited to collaborative atomic structure determinations, molecular genetics, live cell imaging, human tissue engineering and gene targeting approaches. Dr. Green serves as Associate Director for Basic Sciences in the R.H. Lurie Comprehensive Cancer Center.

For more information, please visit the Green Lab website and the faculty profile of Kathleen J Green, PhD.

Publications

See Dr. Green's publications in PubMed.

Contact

Dr. Green

Dr. Green’s laboratory investigates the mechanisms of cholestatic liver injury and the molecular regulation of hepatocellular transport. Current studies are investigating the role of the UPR in the pathogenesis and regulation of hepatic organic anion transport and other liver-specific metabolic functions. We employ genetically modified mice and other in vivo and in vitro models of bile salt liver injury in order to better define the relevant pathways of liver injury and repair; and to identify proteins and genes in these pathways that may serve as therapeutic targets for cholestatic liver disorders.

The laboratory also investigates the mechanisms of liver injury in fatty liver disorders and the molecular regulation of hepatic metabolic pathways. The current focus of these studies includes investigations on the role of the UPR in the pathogenesis of non-alcoholic steatohepatitis and progressive fatty liver disease. We employ several genetically modified mice and other in vivo and in vitro models of fatty liver injury and lipotoxicity. Additional studies include the application of high-throughput techniques and murine Quantitative Trait Locus (QTL) analysis in order to identify novel regulators of the UPR in these disease models.  

Publications

See Dr. Green's publications in PubMed.

For more information, please see Dr. Green's faculty profile.

Contact

Contact Dr. Green at 312-503-1812 or the Green Lab at 312-503-0089

Research Description

The research in my lab is centered on autophagy, a lysosomal degradation pathway essential for nutrient recycling, cellular maintenance and physiological function. Autophagy is induced by various stress conditions and allows cells to adapt to changing nutrient and energy demands through protein catabolism. Malfunction of autophagy is implicated in a variety of diseases such as cancer, neurodegeneration, infection and aging. Our interest focuses on the roles and mechanisms of autophagy in the metabolic regulation of mammals and in the pathogenesis of metabolic disorders in human, including obesity and type 2 diabetes. There are many open questions in this largely unexplored area; our research directions include studies of the functions of autophagy in exercise-induced metabolic benefits and investigation of the molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways in the prevention of metabolic dysregulation.

For lab information and more, see Dr. He's faculty profile and lab website.

Publications

See Dr. He's publications on PubMed.

Contact

Contact Dr. He at 312-503-3094.

Lab Staff

Postdoctoral Fellow

Yoon-Jin Kim, Kenta Kuramoto, Min Wan

Technical Staff

Tong Xiao

Visiting Scholar

Xuan Wang

Research Description

Our studies seek to understand the nature and function of a unique nuclear structure, the perinucleolar compartment (PNC), and its relationship with the malignant phenotype. Our work looks to address the function of the PNC and its significance during malignant transformation in multiple ways.

• Determine the correlation between PNCs and cancer in tissues. In collaboration with Dr. Ann Thor at Evanston Hospital, Northwestern University, we have initiated detection of PNC in breast cancer tissues.
• Investigate the function of the PNC, its relationship with the nucleolus and rRNA synthesis. We are in the process of isolating and identifying additional proteins and RNAs in the PNC.

Identification of activities taking place in the PNC will shed light on the understanding of the function of this structure and its relationship to the nucleolus and the transformed phenotype.

For lab information and more, see Dr. Huang's faculty profile.

Publications

See Dr. Huang's publications on PubMed.

Contact

Contact Dr. Huang at 312-503-4269 or the lab at 312-503-4276.

Lab Staff

Temporary Staff

Chen Wang

Visiting Scholar

Nobuhide Ueki

Research Description

Currently, the laboratory is investigating the mechanisms behind the formation of vascular tumors and vascular anomalies. In particular, the group is interested in the identification of critical regulatory nodes that maintain vascular homeostasis and control endothelial proliferation in the context of flow. An additional focus of the lab is to dissect the molecular interactions between endothelial and tumor cells during the process of metastasis with particular emphasis on endothelial barrier.

For lab information and more, see Dr. Iruela-Arispe's faculty profile.

Publications

See Dr. Iruela-Arispe's publications on PubMed.

Contact

Email Dr. Iruela-Arispe

Research Interests

Our lab is interested in how cytoskeletal signaling, motor proteins and adhesion systems are integrated with chemical signaling pathways to regulate cell behavior and tissue differentiation and disease. The Ji lab studies small G proteins and downstream actin regulatory effectors that participate in enucleation during red cell development.

At the level of the nucleus, the Ji laboratory studies genes involved in erythroid lineage commitment, chromatin condensation and enucleation towards understanding how congenital red cell disorders and leukemia develop. 

For more information, visit the faculty profile of Peng Ji, MD, PhD.

Publications

See Dr. Ji's publications in PubMed.

Contact

Dr. Ji

Research Description

The Kessler laboratory focuses on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system. A major interest of the laboratory has been the role of bone morphogenetic protein (BMP) signaling in both neurogenesis and gliogenesis and in regulating cell numbers in the developing nervous system.  Both multipotent neural stem cells and pluripotent embryonic stem cells are studied in the laboratory. Recent efforts have emphasized studies of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hIPSC). The Kessler lab oversees the Northwestern University ESC and IPSC core and multiple collaborators use the facility. In addition to the studies of the basic biology of stem cells, the laboratory seeks to develop techniques for promoting neural repair in animal models of spinal cord injury and stroke. In particular, the lab is examining how stem cells and self-assembling peptide amphiphiles can be used together to accomplish neural repair. The lab is also using hIPSCs to model Alzheimer’s disease and other disorders. 

For more information see the faculty profile of John A Kessler, MD.

Publications

View Dr. Kessler's full list of publications in PubMed.

Contact

John Kessler, MD

Research Description

Progesterone is essential for the regulation of normal female reproductive function.  Its mode of action is diverse and dependent on the target tissues.  In my lab we are interested in delineating the molecular mechanisms of progesterone action through its receptor, PR in the uterus.  This is done in the context of normal endometrial differentiation, specifically, decidualization, as well as in uterine pathologies, such as endometriosis, endometrial cancer and uterine fibroids.  Interestingly, in these three diseases, progesterone responsiveness is aberrant.

Endometrial cancer is the most common gynecologic cancer diagnosed in the United States with an estimated 40,100 new cases and about 7,500 deaths in 2008.  As risk factors for endometrial cancer increase, the incidence of this disease will also rise, with a paradigm shift to younger ages. In our laboratory, we investigate the role of progesterone receptor in endometrial cancer to understand why progestin therapy is not an effective treatment in all cases of endometrial cancer.

Endometriosis is an estrogen-dependent disorder affecting up to 10% of the female population and 30-50% of infertile women, with no cure and limited therapies. It is often associated with debilitating pelvic pain and infertility. This disease has also been referred to as a “progesterone resistant” disease since the ectopic and eutopic tissues do not respond to progesterone as it does in normal endometrial tissues. Our laboratory is investigating progesterone resistance in endometriosis and identifying specific biological targets for the future development of alternative therapies.

Leiomyoma, also known as uterine fibroids, are benign tumors originating from the myometrium. These tumors can range from a few millimeters to over 20 cm in size. Leiomyomas are common and can occur in up to 77% of women while up to 20% of women suffer from significant morbidity, pain and discomfort and excessive menstrual bleeding. Leiomyomas are the primary indication for over 200,000 hysterectomies in the United States. In our laboratory we are investigating how progesterone promotes growth of leiomyomas by focusing on the non-genomic signaling of progesterone on the PI3K/AKT pathway. These studies are translated to the identification of important signaling molecules that can be targeted using small molecule inhibitors.

For more information, please see Dr. Kim's faculty profile or the Kim Lab website.

Publications

See Dr. Kim's publications in PubMed.

Contact

Contact Dr. Kim at 312-503-5377 or the Kim Lab at 312-503-4762.

Research Description

Cardiovascular development is at the center of all the work that goes on in the Kume lab. The cardiovascular system is the first functional unit to form during embryonic development and is essential for the growth and nurturing of other developing organs. Failure to form the cardiovascular system often leads to embryonic lethality and inherited disorders of the cardiovascular system are quite common in humans. The causes and underlying developmental mechanisms of these disorders, however, are poorly understood. A particular emphasis in our laboratory has recently been the study of cardiovascular signaling pathways and transcriptional regulation in physiological and pathological settings using mice as animal models, as well as embryonic stem (ES) cells as an in vitro differentiation system. The ultimate goal of our research is to provide new insights into the mechanisms that lead to the development of therapeutic strategies designed to treat clinically relevant conditions of pathological neovascularization.

Publications

View Dr. Kume's publications on PubMed.

For more information, visit the faculty profile for Tsutomu Kume, PhD.

Contact Us

Contact Dr. Kume at 312-503-0623 or the Kume Lab at 312-503-3008.

Staff Listing

Austin Culver
MD Candidate
312-503-3008

Anees Fatima
Research Assistant Professor
312-503-0554

Christine Elizabeth Kamide
Senior Research Technologist
312-503-1446

Erin Lambers
PhD Candidate
312-503-5652

Ting Liu
Senior Research Technologist
312-503-3008

Jonathon Misch
Research Technologist
312-503-6153

Research Description

My research lab focuses on translational, basic science projects that aim to develop new therapeutics for ocular angiogenesis independent of vascular endothelial growth factor (VEGF). Neovascular age-related macular degeneration (nAMD) is the leading cause of visual impairment in the developed world. Currently, humanized anti-VEGF antibodies are the gold standard for the treatment of nAMD. Patients currently undergo frequent (up to monthly) injections of anti-VEGF antibodies into the vitreous cavity. The average patient achieves 1-2 lines of visual acuity gain, but 15% of patients still lose vision despite maximal anti-VEGF therapy. Although 15% appears small, given the high prevalence of nAMD, this amounts to 2.5 million patients worldwide. For these poorly responsive patients, there is a clear unmet need for alternative, VEGF-independent therapeutic options.

Macrophage recruitment is central in nAMD pathogenesis. Choroidal neovascularization (CNV) is the pathological hallmark of nAMD. In human histopathology studies of excised CNV membranes, macrophages are readily apparent. In mice, nAMD is modeled by laser-induced injury, which causes CNV membrane formation. Laser-induced CNV formation is robustly inhibited by chemical or genetic macrophage depletion. Based upon these accepted dogma, intravitreal steroids were attempted for nAMD treatment and are unfortunately ineffective. I hypothesize that steroids anti-inflammatory properties are too broad and specific anti-macrophage therapies are necessary. Furthermore, macrophages are highly plastic and heterogenous populations, including pro-inflammatory, pro-restorative, pro-fibrotic, and pro-angiogenic subtypes. My lab’s focus is to identify macrophage heterogeneity in CNV, delineate pro-angiogenic macrophage subtypes, and attempt to develop therapies against pro-angiogenic macrophages for nAMD.

For more information, visit the faculty profile for Dr. Lavine.

Selected Publications

• A. Lavine, Y. Sang, S. Wang, M.S. Ip, N. Sheibani. “Attenuation of choroidal neovascularization by beta(2)-adrenoreceptor antagonism” (2013) JAMA Ophthalmology, 131(3):376-382. (PMID: 23303344)
• Nourinia, M. Rezaei Kanavi, A. Kaharkaboudi, S.I. Taghavi, S.J. Aldavood, S.R. Darjatmoko, S. Wang, Z. Gurel, J.A. Lavine, S. Safi, H. Ahmadieh, N. Daftarian, N. Sheibani. “Ocular safety of intravitreal propranolol and its efficacy in attenuation of choroidal neovascularization.” (2015) Investigative Ophthalmology and Visual Science, 56: 8228-8235. (PMID: 26720475)
• A. Lavine, M. Farnoodian, S. Wang, S.R. Darjatmoko, L.S. Wright, D.G. Gamm, M.S. Ip, N. Sheibani. “beta2-Adrenergic receptor antagonism attenuates CNV through inhibition of VEGF and IL-6 expression” (2017) Investigative Ophthalmology and Visual Sciences, 58 (1): 299-308. (PMID: 28114591)
• M. Hendrick, J. A. Lavine, A. Domalpally, A.D. Kulkarni, M.S. Ip. “Propranolol for proliferative diabetic retinopathy.” (2018) OSLI Retina, 49 (1): 35-40. (PMID: 29304264).
• A. Lavine, A.D. Singh, A. Sharma, K. Baynes, C.Y. Lowder, S.K. Srivastava. “Ultra-Widefield Multimodal Imaging in Primary Central Nervous System Lymphoma with Ophthalmic Involvement.” (2018) Retina, Epub ahead of print. (PMID 30044267)

Contact Dr. Lavine

Lab Phone: 312-503-0487

Glucocorticoids are the most frequently prescribed medicine today and they are indispensable in the treatment of asthma, inflammation and cancer. However, two concerns regarding glucocorticoid use remain unresolved. One is that high-dose or long-term glucocorticoids result in troublesome side effects such as metabolic syndrome and osteoporosis; the other is that some patients do not respond to glucocorticoids. We tackle both questions by examining the glucocorticoid receptor. Translational isoforms of glucocorticoid receptors were recently discovered in our lab and they provide insights into the mechanisms of action of glucocorticoids. Ribosomal shunting and leaky scanning processes generate translational glucocorticoid receptor isoforms. These receptor isoforms have distinct cell-killing and cytokine-suppression capabilities in a bone cancer cell model system. Currently, we are identifying and characterizing the receptor isoforms in different populations of immune cells in diseases such as asthma and cancer. This line of research has implications in several other fields in addition to immunology and oncology. For instance, our findings in glucocorticoid receptor biology have significant impact on research in endocrinology as well.

Publications

View publications on PubMed

For more information visit the faculty profile of Nick Lu, PhD

Contact

Contact Dr. Lu at 312-503-1310 or the Lu Lab at 312-503-1963.

Lab Staff

Jesus Banuelos, BA
PhD Student
312-503-1396

Yun Cao, MD
Senior Research Technologist
312-503-1396

Soon Cheon Shin, PhD
Research Associate
312-503-1396

Postdoctoral fellow jobs and graduate student rotation projects are available.

Research Description

SMA is characterized by the selective degeneration of spinal motor neurons. As the leading genetic cause of infant mortality, SMA affects one in every eight thousand live births. Our group is interested in studying mechanism regulating motor neuron development and function, as well as why motor neurons specifically degenerate in SMA. To address these questions, we use a combination of genetic, biochemical and cell biological approaches and utilize genetically modified mice, induced pluripotent stem (iPS) cells reprogrammed from fibroblasts and zebrafish as model systems. We focus on the regulation of mitochondrial functions in SMA pathogenesis. Based on our findings, we hope to develop new therapeutic strategies for treating SMA.

Dopaminergic neurons located in the ventral midbrain control movement, emotional behavior and reward mechanisms. Dysfunction of these neurons is implicated in Parkinson’s disease, drug addiction, depression and schizophrenia. Our group is interested in the genetic and epigenetic mechanisms regulating dopaminergic neuron functions in disease and aging conditions. We are particularly interested in how aging and mitochondrial oxidative stress contribute to dopaminergic neuron degeneration in Parkinson's disease through transcriptional and epigenetic regulations. We use mouse models, cultured neurons and iPS cells for these studies.

For more information visit Dr. Ma's faculty profile and Dr. Ma's lab website within the Children's Hospital Research Center.

Publications

View Dr. Ma's publications at PubMed

Contact

Email Dr. Ma

Phone 773-755-6339

Lab Staff

Nimrod Miller, PhD, Postdoctoral Fellow

Han Shi, Graduate Student

Brittany Edens, Graduate Student

Kevin Park, Graduate Student

Monica Yang, Undergraduate Student

Aaron Zelikovich, Undergraduate Student

Research Description

The cellular stress response systems guard the proteome from diverse endogenous and environmental insults to maintain the fitness of the organism. Ironically, this pro-survival system can act to the detriment of the host to enable tumor cells accommodate to the myriad stresses associated with malignancy. Our long-term goals are to identify and characterize the systems that promote protein homeostasis, understand how these systems are co-opted and perturbed in malignancy, and ultimately identify means to manipulate them for therapeutic benefit. To accomplish these goals our group bridges biochemical, genetic and chemical biology approaches with systematic high-throughput and genomic methods.

For lab information, publications and more, see Dr. Mendillo’s faculty profile.

Publications

View Dr. Mendillo's publications at PubMed

Contact

Email Dr. Mendillo

Phone 312-503-5685

Co-localization of Nestin and GFAP in the DG of Nestin-EGFP Transgenic Reporter Mice

Research Description

The laboratory led by Richard Miller, PhD, is interested in studying molecular aspects of nerve cell communication. One of our major interests has been to understand the structure and function of calcium channels. The influx of Ca into neurons through these channels is important for many reasons, including the release of neurotransmitters. We have identified a family of molecules that act as Ca channels in neurons and other types of cells. Each of these molecules has slightly different properties that underlie different neuronal functions. We have analyzed the properties of these molecules by examining their electrophysiological properties following their expression in heterologous expression systems and imaging techniques. Furthermore, we have generated calcium channel knockout mice that have interesting properties such as altered pain thresholds, seizures and memory deficits. We have also been interested in how Ca channels can be regulated by the activation of Gprotein coupled receptors. We have been analyzing the interaction of Gprotein subunits with Ca channels using FRET imaging and other techniques.

Other projects in our laboratory are aim to understanding the molecular basis of neurodegenerative disease. We study Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), HIV-1 related dementia and other neuropathological conditions. In the case of HIV-1 infection, we have been examining the properties and functions of HIV-1 receptors on neurons. These receptors are known to be receptors for chemokines -small proteins that are known to direct the functions of the immune system. We have shown that neurons express many types of chemokine receptors and that activation of these receptors can produce both short and long term effects on neurons. Activation of chemokine receptors expressed by sensory neurons produces neuronal excitation and pain. Activation of chemokine receptors on hippocampal neurons has a prosurvival effect, whereas binding of HIV-1 to these receptors induces apoptosis. We are studying the molecular mechanisms that produce this diverse effects with a view to understanding the molecular basis for HIV-1 related dementias.

For lab information and more, see Dr. Miller’s faculty profile.

See Dr. Miller’s blog “The Keys to all Mythologies: Science, Medicine and Magic” to read articles concerning scientific topics of current interest as well as historical accounts of scientific issues.

Publications

See Dr. Miller's publications on PubMed.

Contact

Contact Dr. Miller at 312-503-3211.

Lab Staff

Research Faculty

Abdelhak Belmadani

Postdoctoral Fellow

Dongjun Ren

Graduate Students

Brittany Hopkins, Andrew Shum

Research Description

The laboratory is interested in understanding the mechanisms underlying the pathogenesis and immunoregulation of T cell-mediated autoimmune diseases, allergic disease and rejection of tissue and organ transplants.  In particular, we are studying the therapeutic use of short-term administration of costimulatory molecule agonists/antagonists and specific immune tolerance induced by infusion of antigen-coupled apoptotic cells and PLG nanoparticles for the treatment of animal models of multiple sclerosis and type 1 diabetes, allergic airway disease, as well as using tolerance for specific prevention of rejection of allogeneic and xenogeneic tissue and organ transplants.

For lab information and more, see Dr. Miller's faculty profile.

Publications

See Dr. Miller's publications on PubMed.

Contact

Contact Dr. Miller at 312-503-7674 or the lab at 312-503-1449.

Lab Staff

Research Faculty

Igal Ifergan, Joseph Podojil, Dan Xu

Adjunct Faculty

John Galvin

Postdoctoral Fellows

Gabriel Lorca, Tobias Neef, Haley Titus

Lab Manager

Valerie Eaton

Technical Staff

Sara Beddow, Ming-Yi Chiang, Lindsay Moore

Program Staff

Cynthia Naugles

Visiting Scholars

Daniel Getts

Research Description

Centrioles are microtubule based structures with nine fold symmetry that are involved in both centrosome organization and aster formation during cell division. During the normal cell cycle centrioles duplicate once, generating a mother/daughter pair and in most post-mitotic vertebrate cells the mother centriole then goes on to form the basal body of a sensory cilium. Abnormalities in the duplication of centrioles (and centrosomes) are prevalent in many cancers suggesting a link between centriole duplication and cancer progression. We study what factors limit centriole duplication from a novel direction with the use of Xenopus motile ciliated cells. Ciliated cells are unique among vertebrate cells in that they generate hundreds of centrioles (basal bodies) therefore providing a great system for studying the regulation of centriole duplication. Understanding how nature has overcome the typically tight regulation of centriole duplication will lend insight into the molecular mechanisms of cancer progression.

Tissue development and homeostasis requires dramatic remodeling as new cells migrate into an epithelium.  How migrating cells breakdown junctional barriers during development or during diseases processes such as metastasis is poorly understood at the molecular level.  During the early development of Xenopus embryos, distinct cell types join the outer epithelium in a process called radial intercalation.  We are interested in the molecular mechanisms that regulate both the migration of these cells as well as the tissue remodeling that occurs to accommodate them. 

The ability of ciliated epithelia to generate directed fluid flow is an important aspect of diverse developmental and physiological processes including proper respiratory function. To achieve directed flow, ciliated cells must generate 100-200 cilia that are polarized along a common axis both within and between cells. My lab is currently working towards understanding the molecular mechanisms for how cell polarity is coordinated as well as how individual cilia interpret the cells polarity. We have determined that ciliated cells receive polarity cues via the non-canonical Wnt/Planar Cell Polarity (PCP) pathway, but the details of this are still poorly understood. Additionally, the PCP pathway is known to influence a cells cytoskeleton dynamics and a main goal is to understand how this influences the ability of individual cilia to coordinate their polarity.

For lab information and more, see Dr. Mitchell's faculty profile and lab website.

Publications

See Dr. Mitchell's publications on PubMed.

Contact

Contact Dr. Mitchell at 312-503-9251.

Lab Staff

Postdoctoral Fellows

Caitlin Collins, Jennifer Mitchell, Rosa Ventrella

Technical Staff

Eva Brotslaw, Sun Kim, Ahmed Majekodunmi

Research Description

Most diseases are due to or involve a significant component of inflammation. My lab studies the inflammatory response at the cellular and molecular level. We are focused on the process of diapedesis, the "point of no return" in inflammation where leukocytes squeeze between tightly apposed endothelial cells to enter the site of inflammation. We have identified and cloned several molecules that are critical to the process of diapedesis (PECAM (CD31), CD99, and VE-cadherin) and are studying how they regulate the inflammatory response using in vitro and in vivo models. We have recently described the Lateral Border Recycling Compartment, a novel para-junctional organelle that contains PECAM and CD99 and is critical for diapedesis to occur. We are currently investigating how this compartment regulates diapedesis in the hope of finding novel and highly specific targets for anti-inflammatory therapy.

The “holy grail” of therapy is to develop selective anti-inflammatory agents that block pathologic inflammation without interfering with the body’s ability to fight off infections or heal wounds.  By understanding how endothelial cells at the site of inflammation regulate leukocyte diapedesis, we are hoping to do just that.  We have identified several molecules critical for diapedesis in acute and chronic inflammatory settings that can be genetically deleted or actively blocked to markedly inhibit clinical symptoms (e.g. in a mouse model of multiple sclerosis) and tissue damage (e.g. in a mouse model of myocardial infarction) without impairing the normal growth, development, and health of these mice.  Our inflammatory models include atherosclerosis, myocardial infarction, ischemia/reperfusion injury, stroke, dermatitis, multiple sclerosis, peritonitis, and rheumatoid arthritis. We are also using 4-dimensional intravital microscopy to view the inflammatory response in real time in living animals.

• What are the molecular mechanisms and signaling pathways that endothelial cells use to regulate the inflammatory response?
• How can we therapeutically treat inflammatory diseases without compromising the ability of the immune system to respond to new threats?
• Do circulating tumor cells use the same mechanisms as leukocytes to cross blood vessels when they metastasize?

Our Facilities

We have a high-resolution Perkin Elmer ULTRAVIEW Vox System spinning disk laser confocal microscope in the upright configuration on an Olympus BX51WI fixed stage in my laboratory designed for intravital microscopy.  We can image the ongoing inflammatory response and response to our drugs in real time in anesthetized mice with unprecedented temporal and spatial resolutions.  We presently image inflammation in the cremaster muscle, intestine, and brain.

Of interest to History of Science buffs, we have the original Zeiss Ultrafot II microscope used to film the first movies of neutrophils ingesting bacteria. As you might expect from something built by Zeiss in the first half of the 20^th century, the optics are still fantastic and we use it in our daily work.

Our Successes

Recently we made two major discoveries in endothelial cell inflammatory signaling: Identification of TRPC6 as the cation channel responsible for the endothelial cell calcium flux required for transmigration and description of the CD99 signaling pathway.  Both had eluded discovery for decades.

• Watson, R.L., J. Buck, L.R. Levin, R.C. Winger, J. Wang, H. Arase, and W.A. Muller. 2015. Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte   transendothelial migration. J. Exp. Med. 212:1021-1041.
• Weber, E.W., F. Han, M. Tauseef, L. Birnbaumer, D. Mehta, and W.A. Muller. 2015. TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-1899. PMID:    26392222

Recent Awards

• AAAS Fellow, elected 2010
• Rous-Whipple Award, American Society for Investigative Pathology, 2013
• Ramzi Cotran Memorial Lecture, Brigham and Women’s Hospital, 2014
• Karl Landsteiner Lecture, Sanquin Research Center, Amsterdam, Netherlands, 2016
• Member, Faculty of 1000 Leukocyte Development Section
• American Society for Investigative Pathology (ASIP) Council
• ASIP Research and Science Policy Committee Chair
• North American Vascular Biology Organization (NAVBO) Secretary-Treasurer

Grants Won

• NIH R01 HL046849-26 William A. Muller                     08/01/91 – 05/31/20

  The Roles of Endothelial PECAM and the LBRC in Leukocyte Transmigration

  This study investigates how PECAM-1 and the LBRC regulate transmigration.  We will investigate how PECAM ligation on endothelial cells activates TRPC6 to promote the calcium flux necessary for transmigration (Aim I).  We will identify how endothelial IQGAP1 regulates transmigration by regulating targeted recycling of the LBRC (Aim II).  We will identify how kinesin light chain 1 variant 1 facilitates movement of the LBRC during targeted recycling (Aim III).  All of these Aims include mechanistic studies in vitro and validation studies in vivo using mouse models of ischemia/reperfusion injury in acute inflammation and myocardial infarction.

• NIH R01 HL064774-16 William A. Muller                     04/01/00 – 08/31/20

  Beyond PECAM:  Mechanisms of Transendothelial Migration

  This study investigates the role of PECAM, CD99L2, and CD99 in transendothelial migration.  Aim I will test the hypothesis that leukocytes control the molecular order of transmigration by polarizing PECAM on their leading edge and CD99 on the trailing edge during transmigration.  Aim II will identify the signaling mechanisms by which CD99L2 regulates transmigration.  Aim III will identify the signaling mechanisms by which CD99 regulates targeted recycling of the LBRC and transmigration downstream of Protein Kinase A.  All Aims have in vitro mechanistic studies and in vivo validation studies using intravital microscopy in the cremaster muscle circulation and a murine model of ischemia/reperfusion injury in myocardial infarction.

For more information, visit the faculty profile of William A Muller, MD, PhD

Publications

View Dr. Muller's publications at PubMed

Staff

Research Assistant Professors

• David Sullivan, PhD d-sullivan@northwestern.edu
• Annette Gonzalez, PhD a-gonzalez2@northwestern.edu
• Tao Fu, PhD t-fu@northwestern.edu

• Ayush Batra, MD batra@nm.or

• Neil Nadkarni, MD nadkarni@northwestern.edu

• Prarthana Dalal (MD/PhD) PrarthanaDalal@u.northwestern.edu
• Nakisha Rutledge Rutledge2012@u.northwestern.edu
• Margarette Clevenger MargaretteClevenger2021@u.northwestern.edu

• Clifford Carpenter, PhD clifford-carpenter@northwestern.edu

• Corinne Rodman CorinneRodman2018@u.northwestern.edu
• Faith Ogungbe n6n8u3@u.northwestern.edu

Contact

Bill Muller

Office: Ward Building, Room 3-126
303 East Chicago Avenue
Chicago, IL 60611-3008

Phone: (312) 503-0436
Fax: (312) 503-8249
E-mail:  wamuller@northwestern.edu

Lab: Ward Building 3-070 and 3-031
Lab Phone: (312) 503-5200
Lab Fax: (312) 503-2630

Research Description

Our research focuses on infection by Human Immunodeficiency Virus type 1 (HIV-1), a retrovirus and causative agent of acquired immunodeficiency syndrome (AIDS). In addition to suppressing the immune system, rendering victims susceptible to opportunistic infections, HIV-1 can cross the blood-brain barrier and cause serious damage to the central nervous system, ultimately leading to HIV-associated dementia.

We are interested in how HIV-1 particles move within infected cells, including brain cell types such as microglia. Our work focuses on how the virus exploits host microtubules, the intracellular filaments that mediate cargo trafficking to different subcellular sites within the cell.

Our earlier work, employing a variety of screening approaches, identified a number of host proteins involved in cytoskeletal regulation and motor function as playing key roles in the early stages of HIV-1 infection. This includes Ezrin-Radixin-Moesin (ERM) proteins, which cross-link the actin and microtubule cytoskeletons. In exploring their role in HIV-1 infection, we identified the first biological function for the host protein, PDZD8, demonstrating that it binds ERMs to control microtubule stability. Furthermore, we uncovered that PDZD8 is a direct target for the HIV-1 protein, Gag.

Other work in our laboratory has shown that HIV-1 can induce the formation of highly stable microtubule subsets to facilitate early HIV-1 trafficking to the nucleus. We are interested in the role played in this process by proteins such as PDZD8, as well as a family of specialized microtubule regulatory proteins called +TIPs, which accumulate at the ends of dynamically growing microtubule filaments to control their growth and stability. We are also interested in the function of microtubule motors and cargo adaptor proteins in HIV-1 infection. In particular, we are exploring how Fasciculation and Elongation factor Zeta-1 (FEZ-1), a kinesin-1 adaptor protein that is highly expressed in neurons, functions to control HIV-1 infection. Our work employs a range of approaches, including biochemical characterization of protein-protein interactions as well as live imaging of fluorescently-labeled HIV-1 particles as they move within infected cells.

The ultimate goal of our work is to understand the molecular basis behind how microtubules, regulators of microtubule dynamics and microtubule motor proteins function to enable HIV-1 movement to and from the nucleus.

For lab information and more, see Dr. Naghavi's faculty profile and lab website.

Publications

See Dr. Naghavi's publications at PubMed.

Contact

Contact Dr. Naghavi at 312-503-4294.

Lab Staff

Postdoctoral Fellows

Qingqing Chai, Feng Gu, Viacheslav Malikov, Sahana Mitra, Gina Pisano, Eveline Santos da Silva, Shanmugapriya Swamy

Technical Staff

Kayla Schipper

Research Description

This is an exciting time for cancer biology especially with the advent of epigenetics and chromatin biology. New molecules with tumor suppressive or oncogenic roles are currently identified and characterized paving the way for new therapeutic ways but at the same time, posing new challenges for researchers. This area of cancer epigenetics is my personal and laboratory's focus. To study this perplexing biology we use patient samples and disease-relevant mouse models.

The Ntziachristos laboratory studies the mechanistic aspects of oncogenesis with an emphasis on transcriptional and epigenetic regulation of acute leukemia. Important questions are related to how oncogenes interact with each other and with epigenetic modulators to influence gene expression programs as well as how their function is related to tri- dimensional (3D) structure of the nucleus and other biological aspects of cancer cells, like metabolism. To address these questions we use high-throughput molecular and cell biology techniques like ChIP-Seq, RNA-Seq, 4C-Seq and HiC, fluorescent in situ hybridization and biochemical analysis in cell lines and primary cells of human origin and tissues of mouse models of disease. In addition to understanding cancer biology these finding help us design and test targeted therapies in preclinical models of leukemia.

For lab information and more, see Dr. Ntziachristos's faculty profile and lab website.

Publications

See Dr. Ntziachristos's publications at PubMed.

Contact

Contact Dr. Ntziachristos at 312-503-5225 or Searle 6-523

Another interest lies in the study of RNA interference and based on toxic RNAs to development a novel form of cancer treatment. 

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Marcus Peter, PhD or the laboratory's website.

Contact Us

Contact Dr. Peter at 312-503-1291 or the Peter Lab at 312-503-2883.

Lab Staff

Quan Gao
Postdoctoral Fellow

Monal Patel
Postdoctoral Fellow

Qadir Syed
Postdoctoral Fellow

Ashley Haluck-Kangas
Graduate Student

Will Putzbach
Graduate Student

Bryan Bridgeman
Research Technician

Calvin Law
Research Technician

Andrea Murmann
Research Assistant Professor 

Cell signaling is part of an intricate system of events activated by various stimuli that coordinate cell responses. Our laboratory is interested in unveiling pathways involved in cancer development in order to target them and control cancer progression. For over two decades, Dr. Platanias’ laboratory has identified several cellular cascades activated by IFN, ATRA and arsenic. Our research on Type I IFN found an essential role for SKAR protein in the regulation of mRNA translation of IFN-sensitive genes and induction of IFN-α biological responses. We also provided evidence for unique function of mTORC2 complex in inducing Type I IFN response. Our studies on arsenic signaling revealed a direct binding of this compound to a kinase called AMPK as a mechanism underlying its anti-leukemic activity. Other work included the activation of biological responses by BCR-ABL oncoprotein through the mTOR pathway. Dr. Platanias’ laboratory is also involved in testing new compounds in combination with approved therapies in order to identify synergy and improve the risk/benefit ratios of current therapeutic regimens for patients.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Leonidas Platanias, MD, PhD.

Contact Us

Contact Dr. Platanias at 312-908-5250 or the Platanias Lab at 312-503-4500.

Lab Staff

Dirim Arlsan, PhD
Post-Doctoral Fellow
312-503-4500

Elspeth Beauchamp, PhD
Post Doctoral
312-503-4500

Jonathan Bell
Graduate Student
312-503-0292

Gavin Timothy Blyth
Lab Technician
312-503-4500

Dany Curi
Post Doctoral Fellow
312-503-0292

Frank Eckerdt
Research Assistant Professor
312-503-0292

Asneha Iqbal
Post Doctoral Fellow
312-503-0292

Ewa Kosciuczuk
Post Doctoral Fellow
312-503-4500

Barbara Kroczynska
Research Assistant Professor
312-503-4500

Swarna Mehrotra
Research Associate
312-503-4500

Diana Saleiro
Post Doctoral Fellow
312-503-4500

Antonella Sassano
Research Assistant Professor
312-503-4500

Our laboratory has identified the upregulation of the anti-apoptotic protein, Flice Like Inhibitory Protein (FLIP), during monocyte to macrophage differentiation. They have demonstrated that FLIP is highly expressed in the rheumatoid joint and is responsible for protecting RA macrophages from Fas-mediated apoptosis. These studies have been extended to examine the in vivo relevance of FLIP to macrophage biology. Mice with FLIP conditionally deleted in myeloid cells are not capable of developing macrophages. The relevance of these observations to chronic inflammatory arthritis is currently under investigation. Since macrophages are critical to the pathogenesis of RA, future studies will focus on macrophage specific FLIP as a therapeutic target in RA.

Additional studies in the laboratory are focusing on the role of endogenous TLR ligands as potential contributors to the persistent activation of macrophages in the RA joint. The Pope laboratory has identified an endoplasmic reticulum (ER) localized protein called gp96, which binds to TLRs within ER of macrophages and correctly transports them to the cell membrane or endosome. In patients with RA, gp96 is highly increased in RA synovial tissue, particularly in macrophages, and is found in RA synovial fluid in high concentrations. gp96 binds to the extracellular domains of TLR2 and TLR4. Both recombinant gp96 and gp96 present in the RA synovial fluid is capable of activating TLR2 and to a lesser degree TLR4. Ongoing studies in the laboratory are further characterizing the mechanisms by which gp96 and other endogenous TLR ligands might contribute to the pathogenesis of RA employing in vitro studies utilizing cells isolated from the joints of patients with RA and experimental murine models of RA

Additional studies are ongoing in the laboratory to further identify and define the potential clinical relevance of endogenous TLR ligands in the RA joint employing three approaches which are dependent upon binding to endogenous ligands to TLRs. These approaches include the use of recombinant IgG Fc-TLR2 and IgG Fc-TLR4 to pull down TLR ligands from cells isolated from the RA joint; the use of HEK-TLR2 and HEK-TLR4 cells to bind endogenous TLR ligands in RA synovial fluid which will be identified employing a proteomics approach and utilizing a yeast 2 hybrid system where mRNA from inflammatory RA synovial tissue has been employed to develop the bait, while the extracellular domains to TLR2 and TLR4 are being used as the prey. Each of these approaches have identified candidate molecules which are being further characterized for a potential role in the pathogenesis of RA.

Publications

View Dr. Pope's publications at PubMed

For more information related to the Pope Lab’s work, please see Richard M. Pope’s, MD, profile.

Contact

Contact Dr. Pope at 312-503-8003 or the Pope Lab at 312-908-1965

Research Description

Research in the laboratory of Murali Prakriya, PhD, is focused on the molecular and cellular mechanisms of intracellular calcium (Ca2+) signaling. Ca2+ is one of the most ubiquitous intracellular signaling messengers, mediating many essential functions including gene expression, chemotaxis and neurotransmitter release. Cellular Ca2+ signals generally arise from the opening of Ca2+ permeable ion channels, a diverse family of membrane proteins. We are studying Ca2+ signals arising from the opening of a Ca2+ channel sub-type known as the store-operated Ca2+ channel (SOC). SOCs are found in the plasma membranes of virtually all mammalian cells and are activated through a decrease in the calcium concentration ([Ca2+]) in the endoplasmic reticulum (ER), a vast membranous network within the cell that serves as a reservoir for stored calcium. SOC activity is stimulated by a variety of signals such as hormones, neurotransmitters and growth factors whose binding to receptors generates IP3 to cause ER Ca2+ store depletion.

The best-studied SOC is a sub-type known as the Ca2+ release activated Ca2+ (CRAC) channel. CRAC channels are widely expressed in immune cells and generate Ca2+ signals important for gene expression, proliferation and the secretion of inflammatory mediators. Loss of CRAC channel function due to mutations in CRAC channel genes leads to a devastating immunodeficiency syndrome in humans. A major effort in our lab is to understand the molecular mechanisms of CRAC channel function.

Recent Findings

Despite the fact that SOCs are found in practically all cells, their properties and functions outside the immune system remain largely unexplored. In order to fill this gap, we have begun investigation of SOC properties and their functions in two major organ systems: in the brain and the lung.

• Neural stem cells (NSCs) express SOCs; robust Ca2+ signals arise from their activation, indicating that SOCs are a major route of Ca2+ entry in NSCs
• CRAC channels serve as a major route of Ca2+ entry in lung epithelial cells; CRAC channel activation leads to robust activation of NFAT and the production of proinflammatory cytokines

For lab information and more, see Dr. Prakriya’s faculty profile and lab website.

Publications

See Dr. Prakriya's publications on PubMed.

Contact

Contact Dr. Prakriya at 312-503-7030.

Lab Staff

Research Faculty

Megumi Yamashita

Postdoctoral Fellows

Mehdi Maneshi, Nisha Shrestha, Shogo Tsujikawa, Priscilla Yeung

Graduate Students

Tim Kountz, Michaela Novakovic, Andrew Shum, Ann Toth

Technical Staff

Martinna Raineri Tapies

Vimentin is also involved in all stages of cancer development, from PI3K/AKT and Erk pathway regulation in tumerigenesis, to its defining role in epithelial-to-mesenchymal transition, to metastatic cell invasion and migration, making it an intriguing therapeutic target. Our purpose in examining vimentin’s role in lung cancer is to determine whether its inhibition might be of benefit to patients.

Publications

View our lab’s publications in PubMed.

To learn more, please visit the faculty profile pages of Karen M. Ridge, PhD

Visit the Ridge Lab Website

Contact Us

Email Dr. Ridge
Phone 312-503-1648 or the Ridge Lab at 312-503-0403

Lab Staff

Alexandra Berr
Graduate Student
312-503-0403

Yuan Cheng
Research Technologist 2
312-503-0403

Mark Ciesielski
Research Technologist 1
312-503-0403

Bria Coates, MD
Assistant Professor
312-227-4800

Jennifer Davis
Research Technologist I
312-503-0403

Francisco Gonzalez, MD
Postdoctoral Research Fellow

Grant Hahn, MD
Critical Care Medicine Fellow

Jennifer Yuan-Shih Hu, PhD
Postdoctoral Research Fellow
312-503-4845

Clarissa Masumi Koch, PhD
Postdoctoral Research Fellow
312-503-0403

Dale Shumaker, PhD
Research Assistant Professor
312-503-1918

Margaret Turner
Research Technologist 1
312-503-4845

Research Description

Neurons communicate with each other at synapses, extremely specialized and plastic structures able to adjust both quantitatively and qualitatively to correctly respond to a changing environment. The majority of neuronal communication is mediated by the activation of glutamate receptors (GluRs), which triggers mechanisms able to induce changes at synaptic level that are thought to underlie higher cognitive functions. Accordingly, GluRs are extremely well regulated in a cell- and synapse-specific manner. Several mechanisms including the control of expression/degradation level, intracellular trafficking or channel properties work coordinately to regulate GluRs. Not surprisingly, an aberrant GluR trafficking and/or function is a shared hallmark for many neurological disorders, including Alzheimer’s disease, Huntington’s disease, schizophrenia and autism.

The Sanz-Clemente Lab is interested in the molecular mechanisms underlying GluR trafficking in normal and altered conditions. We use a multidisciplinary approach including biochemistry, cell and molecular biology, pharmacology as well as a variety of imaging techniques and the analysis of genetically-altered mouse lines for elucidating how GluRs are controlled during development, in response to experience or other stimuli and what is their impact on synaptic function. Similarly, we investigate how the dysregulation of these mechanisms lead to synaptic alterations and, eventually, to neurological disorders. Current research focuses on NMDA Receptor (NMDAR) regulation and its role in the pathogenesis of Alzheimer’s disease.

Recent Findings

The synaptic NMDAR subunit composition changes from predominantly GluN2B-containing to GluN2A-containing NMDARs during synaptic maturation and in response to activity and experience. This is an evolutionally conserved process that occurs in many brain areas and has important consequences in synaptic plasticity and intracellular signaling pathways.

• We have identified the phosphorylation within the GluN2B PDZ ligand by casein kinase 2 as a critical determinant for the NMDAR subunit switch, by promoting GluN2B internalization and allowing GluN2A insertion into synaptic sites.
• We have reported a novel structural role for CaMKII, acting as a scaffolding protein able to couple GluN2B and casein kinase 2 in response to activity, which controls NMDAR synaptic content.

Current Projects

• Investigating the molecular mechanisms controlling the balance between synaptic and extrasynaptic NMDARs and its role in the pathogenesis of Alzheimer’s disease
• Investigating the molecular mechanisms underlying synapse unsilencing during development
• Studying the differential reorganization of synaptic protein content by typical and atypical antipsychotic drugs

For lab information and more, see Dr. Antonio Sanz-Clemente's faculty profile and lab website.

Publications

See Dr. Sanz-Clemente's publications on PubMed.

Contact

Contact Dr. Sanz-Clemente at 312-503-4896.

Lab Staff

Graduate Students

Andrew Chiu, Pavla Hubalkova

Technical Staff

Levi Barse

Research Description

The pattern of gene expression in eukaryotic cells is strongly influenced by interactions with neighboring cells. When cell-cell interactions are perturbed, changes in cellular gene activity are often observed. In the vertebrate retina, inherited or acquired rod and cone degeneration results in disruption of normal interactions between photoreceptors and their support cells, the Müller cells. Under these conditions many genes such as the glial intermediate filament protein (GFAP) gene, ciliary neurotrophic factor (CNTF) gene and basic fibroblast growth factor (bFGF) gene are upregulated in neighboring Müller cells.

We use techniques such as single cell RT-PCR and differential display to study changes in gene expression patterns in Müller cells. Major goals of our current research are to elucidate the molecular mechanisms responsible for transcriptional activation and to determine the extracellular inductive signal and the signal transduction pathways involved. Our recent cell transfection studies and experiments with GFAP-lacZ transgenic mice suggest that GFAP gene activation in Müller cells is regulated by a cell type-specific, inducible enhancer and that GFAP gene is activated through the JAK-STAT pathway. The work on gene regulation is crucial for development of strategies for using Müller cell-specific promoters to test the biological effects of growth factors and cytokines in animals models of retinal degeneration and more importantly for designing cell type-specific vectors for targeted delivery in gene therapy.

A second project is concerned with molecular cloning, regulation and function of neurotransmitter transporters—a family of membrane proteins that are involved in the uptake of neurotransmitters. We are particularly interested in the role of taurine and glutamate transporters in retinal ischemia and glutamate neurotoxicity. We have already cloned and characterized GABA, taurine and glutamate transporters from retina. We have also localized the transporters to specific retinal cell types and shown that phosphorylation may play a key role in regulating transporter function.

For more information visit Dr. Sarthy's faculty profile page.

Publications

View Dr. Sarthy's publications at PubMed

Contact

Email Dr. Sarthy

Phone 312- 503-3031

Research Description

Our long-term objectives are to further define the molecular interactions and physiological functions of transcriptional activators and co-activators involved in the nuclear control of the respiratory apparatus. Current work in the lab combines molecular and biochemical approaches with the development of cellular and transgenic models to understand in vivo regulatory pathways and mechanisms.

For lab information see Dr. Scarpulla's faculty profile.

Publications

See Dr. Scarpulla's publications on PubMed

Contact

Contact Dr. Scarpulla at 312-503-2946.

Research Description

Our laboratory examines the signals that modulate fibrogenesis. This process is important in promoting normal healing but, when uncontrolled, leads to excessive scar formation such as occurs in chronic progressive cardiovascular or kidney disease. Our studies center upon the role of the Smad signal transduction pathway in extracellular matrix accumulation. We are investigating the mechanism(s) by which transforming growth factor (TGF)-ß stimulates collagen accumulation by the human kidney mesangial cells that are central to the scarring of the renal filter in disease states.

We have determined that the TGF-ß-specific Smad pathway is modulated by interaction with multiple additional signaling mechanisms, including those related to ERK MAP kinase, phosphatidyl inositol-3-kinase, protein kinase C and cytoskeletal rearrangement. Cross-talk amongst these pathways provides a complex milieu for the cellular regulation of fibrogenesis. Characterizing the precise patterns of interaction among signaling pathways that are usually studied in isolation offers our lab the opportunity to define unique events that determine tissue specificity.

Presently, we have two major projects in the lab.  In one, we are examining the role of Smad anchor for receptor activation (SARA) in regulating cell phenotype and function.  In the other, we are examining how cell interaction with the extracellular matrix leads to the activation of specific signaling pathways that promote fibrogenesis.  We recently reported that integrin-mediated, cell adhesion-dependent activation of focal adhesion kinase (FAK) plays an essential role in specific phosphorylations of the Smad3 molecule and in TGF-ß-stimulated collagen expression.

For more information, visit the faculty profile of H. William Schnaper or go to the Schnaper Lab website.

Publications

View Dr. Schnaper's publications at PubMed

Contact

Email Dr. Schnaper

Phone 312-503-1180

Lab Staff

Graduate Students

Bethany Baumann

Research Description

Our lab is interested in the molecular mechanisms of oxygen sensing and the importance of this process for embryonic development, tissue responses to hypoxia and tumor angiogenesis. We are testing the hypothesis that the mitochondria play a central role in detecting cellular oxygenation and signal the onset of hypoxia by releasing reactive oxygen species (ROS). These signals trigger downstream signal transduction pathways responsible for the transcriptional and post-translational responses of the cell. Transcriptional activation of genes by Hypoxia-Inducible Factor-1 confers protection against more severe hypoxia by augmenting the expression of glycolytic enzymes, membrane glucose transporters and other genes that tend to augment tissue oxygen supply by increasing the release of vascular growth factors such as VEGF, erythropoietin and vasoactive molecules that augment local blood flow. Current experiments are aimed at improving our understanding of how oxygen interacts with the mitochondrial electron transport chain to amplify ROS production and clarifying the targets that they act on to stabilize HIF and activate transcription.

In specific tissues, oxygen sensing is essential for normal function, but it can also contribute to disease pathogenesis.  For example, during mammalian development, the lung tissue is hypoxic and blood flow is restricted in the pulmonary circulation in order to prevent escape of oxygen from the pulmonary capillaries to amniotic fluid.  At birth, inflation of the lung with air causes an increase in lung oxygen levels, which triggers relaxation of pulmonary arteries.  In Persistent Pulmonary Hypertension of the Newborn, failure of the pulmonary circulation to dilate results in elevated pulmonary arterial pressures and significant lung gas exchange dysfunction.  We are testing the hypothesis that pulmonary vascular cells sense O2 at the mitochondria and that ROS released from those organelles trigger an increase in cytosolic calcium, which causes smooth muscle cell contraction.  In adult patients with hypoxic lung disease, similar activation of hypoxic vasoconstriction can lead to chronic pulmonary hypertension, which can progress to right heart failure.  A fuller understanding of the mechanisms of oxygen sensing in health and disease may lead to insights into therapeutic inhibition of this response in disease states.

In solid tumors, consumption of oxygen by highly metabolic tumor cells leads to hypoxia and threatens glucose supplies.  Hypoxic tumor cells retain their oxygen sensing capacity and turn on expression of HIF-dependent genes, leading to tumor angiogenesis and increased blood supply, which permits further growth.  We are currently exploring the hypothesis that the mitochondrial oxygen sensor is required for this response using pursuing genetic models.  A better understanding of how tumor cells detect hypoxia could lead to the discovery of therapeutic approaches that would prevent detection of hypoxia and thereby prevent tumor progression.

For more information visit Dr. Schumacker's faculty profile page

Publications

View Dr. Schumacker's publications at PubMed

Contact

Email Dr. Schumacker

Phone 312-503-1476

Research Description

The development of organs during embryogenesis and their repair during adulthood are biological problems of very practical importance for regenerative medicine.

Using both newt and zebrafish model organisms that naturally rebuild lost structures as adults, we identified evolutionarily conserved gene activities indicative of a molecular signature of regeneration. Particularly, we found the dynamic remodeling of the extracellular matrix (ECM) to be key in instructing cell behaviors that are critical for initiating and maintaining regenerative processes. These findings point to new opportunities for the enhancement of regenerative wound healing in mammals through the manipulation of the local extracellular environment.

As a new research direction, we are studying an unexpected hyperactive blood clotting phenotype in mice deficient for the actin-associated protein Pdlim7. The Pdlim7 knockout mouse provides strong translational opportunities as a novel model to better understand the causes and possible treatments of hypercoagulopathies.

For more information visit the faculty profile of Hans-Georg Simon, PhD.

Publications

View all publications on PubMed

Contact

Email Dr. Simon

Phone Dr. Simon at 773-755-6391 or the Simon Lab at 773-755-6372.

Research Description

We investigate the relationship between infection of the nervous system by herpesviruses and disease outcome. Some of the most traumatic diseases – including polio, rabies and encephalitis – result from infections of the nervous system.  In contrast, herpesviruses are highly proficient at infecting the nervous system, yet normally do not cause neurological disease.  This is achieved in part by self-imposed restrictions encoded within the viruses that limit viral reproduction and prevent dissemination into the brain.  For the individual, this results in a relatively benign infection, yet the virus becomes a life-long occupant of the nervous system that will periodically reemerge at body surfaces to infect others. Unfortunately, this infectious cycle can go awry resulting in several forms of severe disease (i.e. keratitis and encephalitis).

We have pioneered methods to genetically manipulate herpesviruses and visualize individual viruses in living neurons. Using these methods, we are studying the mechanisms by which the virus achieves its stringently controlled infectious cycle. Current genetic manipulations are based on a full-length infectious clone of the herpesvirus genome. The clone was made as a bacterial artificial chromosome (BAC) in E. coli. Transfection of purified E. coli BAC plasmid into permissive eukaryotic cells is sufficient to initiate viral infection, allowing for immediate examination of viral mutant phenotypes in a variety of biological assays.  For example, by fusing the green fluorescent protein (GFP) to a structural component of the viral capsid, individual viral particles can be tracked within the axons of living neurons during both entry and egress phases of the infectious cycle. Studies in culture can be complemented by examining the pathogenesis of mutant viruses in rodent models of infection.

Using these methods, we have discovered key aspects of cellular infection, viral assembly and intracellular transport. Looking forward, we are continuing to pursue our multidisciplinary approach of combining neuroscience, cell biology, bacterial genetics and virology to better understand these important pathogens.

For lab information and more, see Dr. Smith's faculty profile.

Publications

See Dr. Smith's publications on PubMed.

Contact

Contact Dr. Smith at 312-503-3745 or the lab at 312-503-3744.

Lab Staff

Research Faculty

Sarah Antinone 

Postdoctoral Fellows

Oana Maier

Graduate Students

Osefame Ewaleifoh, Caitlin Pegg, Laura Ruhge

Technical Staff

Austin Stults 

Research Description

Our research program is aimed at understanding the genetic program that underlies the pathogenesis of Glioblastoma multiforme (GBM), the most prevalent and malignant form of brain cancer. Applying a combination of cell/molecular biology, oncogenomic and mouse engineering approaches, we are dedicated to systematically characterize novel gliomagenic oncogenes and tumor suppressors. We will functionally delineate and validate these pathways using cell culture and animal models and develop novel nanotechnological approaches to target these aberrations in established tumors.

For more information see the faculty profile of Alexander H Stegh MD, PhD, or visit  the Alexander H. Stegh Lab website.

Recent Publications

View Dr. Stegh's full list of publications at PubMed

Contact

Alexander Stegh, MD, PhD, at 312-503-2879

Research Description

Immune cells are critical for host defense, however immune cell infiltration of mucosal surfaces under the conditions of inflammation leads to significant alteration of the tissue homeostasis. This includes restructuring of the extracellular matrix and alterations in cell-to-cell adhesions. Particularly, immune cell-mediated disruption of junctional adhesion complexes, which otherwise regulate epithelial cell polarity, migration, proliferation and differentiation can facilitate both tumorigenesis and cancer metastasis. Our research thus focuses on understanding the mechanisms governing leukocyte induced tissue injury and disruption of epithelial integrity as potential risk factors for tumor formation, growth and tissue dissemination.

For publication information see PubMed and for more information see Dr. Sumagin's faculty profile page or laboratory site.

Contact information

Ronen Sumagin, PhD
Assistant Professor in Pathology
312-503-8144
Email:  ronen.sumagin@northwestern.edu

Seasonal influenza infection affects a significant proportion of the population in the US and worldwide and while most patients infected with influenza A virus (IAV) recover without sequelae, in many patients influenza virus infection may cause ARDS. Alveolar epithelial cells (AEC) are targets for IAV and play an important role in mounting the initial host response. The Sznajder Lab hypothesizes that the alveolar epithelium plays an important effector role in protecting the lung from severe injury. Findings indicate that the degradation of PKCζ, which triggers the down-regulation of Na,K-ATPase, by the E3 ligase HOIL-1L decreases AEC death.  HOIL-1L is a member of the Linear Ubiquitination Assembly Complex (LUBAC) and the lab studies whether LUBAC participates in the modulation of the inflammatory intensity in the lung epithelium during IAV infection. Also, they are investigating the mechanisms by which modest inhibition of the Na,K-ATPase,  whether pharmacologic inhibition of the Na,K-ATPase by cardiotonic steroids such as ouabain are protective by inhibiting virus replication.

Studies suggest that signals from the injured lung during IAV infection disrupt skeletal muscle proteostasis and contribute to skeletal muscle dysfunction. The slower recovery of the skeletal muscle function in aged mice during IAV pneumonia is the consequence of diminished proteostatic reserve in cells responsible for regenerating the damaged skeletal muscle.

Hypercapnia (high pCO₂) is observed in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), broncho-pulmonary dysplasia and advanced neuromuscular diseases. The lab hypothesizes that hypercapnia promotes the ubiquitin-proteasome mediated muscle degradation and impairs the function of muscle satellite cells required for its regeneration.

Alveolar fluid reabsorption is effected by vectorial Na⁺ transport via apical Na⁺ channels and basolateral Na,K-ATPase of the alveolar epithelium. We and others have reported that β-adrenergic agonists upregulate the Na,K-ATPase in AEC  by increasing the traffic and recruitment of Na,K-ATPase containing vesicles into the cell membrane, resulting in increased catalytic activity. Moreover, GPCR-mediated upregulation of the Na,K-ATPase resulted in increased alveolar fluid clearance in normal lungs and in rodent models of lung injury.  We are investigating mechanisms of Na,K-ATPase regulation and active Na⁺ transport in lungs which will help with the design of new strategies to increase lung edema clearance.

Publications

View Dr. Sznajder's publications on PubMed

For more information visit the faculty profile of Jacob Sznajder, MD.

Contact

Contact Dr. Sznajder at 312-908-7737 or the Sznajder Lab at 312-503-1685.

Lab Staff

Laura Brion, PhD
Visiting Scholar
312-503-1685

Ermelinda Ceco, PhD
Postdoctoral Research Fellow
312-503-1685

Nina Censoplano, MD
Fellow, Pediatric Critical Care
312-503-1685

Laura A Dada, PhD
Research Associate Professor
312-503-5397

Jeremy Katzen, MD
Research Fellow
312-503-1685

Emilia Lecuona, PhD
Research Associate Professor
312-503-5397

Natalia Magnani, PhD
Postdoctoral Research Fellow
312-503-1685

Masahiko Shigemura, PhD
Postdoctoral Research Fellow
312-503-1685

Lynn C. Welch
Research Laboratory Manager
312-503-1685

Our research program focuses on diseases of the esophagus, which are among the most common ailments in the United States and throughout the world, resulting in significant morbidity, mortality and healthcare expenditures. Understanding the molecular mechanisms underlying esophageal disease pathogenesis is crucial and will lead to considerable improvements in the diagnosis and the treatment of esophageal diseases. Although alterations of the microenvironment have been described in esophageal diseases, such as esophageal cancer and esophagitis, our knowledge of the molecular mechanisms that mediate changes in the microenvironment and that regulate epithelial-stromal interactions in the context of esophageal diseases is still very limited.

Our research program focuses on two key inflammatory pathways: the IKKβ/NFκB and STAT3 pathways. We employ novel in vitro and in vivo models and state-of-the-art methodology to define key factors regulating epithelial-epithelial and epithelial-stromal signaling in the esophagus. More specifically, our goal is to better understand:

1. How epithelial IKKb regulates the balance between angiogenic and angiostatic factors and how it affects the stromal microvasculature
2. How epithelial IKKb contributes to the phenotypic heterogeneity of stromal fibroblasts
3. How epithelial IKKb controls the recruitment of immune cells
4. The complex interplay existing between IKKb and STAT3 signaling pathways

We expect that these investigations will uncover novel diagnostic and therapeutic targets for esophageal diseases.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Marie-Pier Tetreault, PhD.

Contact Us

Email Dr. Tetreault

Contact the Tetreault Lab at 312-503-1915

Research Interests

The Edward Thorp Lab studies the crosstalk between immune cells and the cardiovascular system and, in particular, within tissues characterized by low oxygen tension or associated with dyslipidemia, such as during myocardial infarction. In vivo, the lab interrogates the function of innate immune cell phagocytes, including macrophages, as they interact with other resident parenchymal cells during tissue repair and regeneration. Within the phagocyte, the influence of hypoxia and inflammation on intercellular and intracellular signaling networks and phagocyte function are studied in molecular detail. Taken together, our approach seeks to discover and link basic molecular and physiological networks that causally regulate disease progression and in turn are amenable to strategies for the amelioration of cardiovascular disease.

Publications

For additional information, visit the Thorp Lab site or view the faculty profile of Edward B Thorp, PhD.

View Dr. Thorp's publications at PubMed

Contact

Contact the Thorp lab at 312-503-3140.

Lab Staff

Shuang Zhang
PhD student
312-503-3140

Xin-Yi Yeap, MS
Lab Manager and Microsurgery
312-503-3140

Research Description

Animal development requires proper specification of different cell types and, at the same time, their organization in to multicellular arrangements such as tissues and organs. My laboratory investigates the mechanisms that control morphogenetic processes in vertebrate embryo. We are studying these processes in the zebrafish (Danio rerio) using a combination of genetic analysis with embryological and molecular methods. The transparency of zebrafish embryos together with the generation of fluorescent transgenic animals allows us to use high-resolution confocal microscopy for in vivo analysis of cell behaviors. Moreover, similarities in developmental programs among all vertebrates make zebrafish an excellent model for investigating human diseases and development.

We are focusing current efforts on the mechanisms that shape the zebrafish head skeleton. We are particularly interested in the role of non-canonical Wnt signaling in cartilage morphogenesis. Mutants with altered non-canonical Wnt signaling pathways exhibit similar cell behavior defects during gastrulation and cartilage morphogenesis. This observation led to the hypothesis that non-canonical Wnt signaling controls cartilage element morphology by modification of chondrocyte behavior. My work on the characterization of the zebrafish knypek gene has revealed a new role for glypicans (heparan sulfate proteoglycan) in controlling morphogenetic movements during gastrulation by promoting non-canonical Wnt11 signaling. We are investigating the function of non-canonical Wnts and their potential co-receptors, glypicans, in chondrocyte differentiation and polarization. Because the initial steps in craniofacial development are similar in all vertebrates, these studies will help understand genetic basis for relatively frequent congenital anomalies causing abnormal development of the hard and soft tissue of the head and neck.

We are also interested in the developmental roles of other glypicans, as these extracellular proteins can play an essential role by interaction with growth factors, chemokines, extracellular matrix proteins, enzymes and enzyme inhibitors. Glypicans can be involved in regulation of ligand-receptor interactions and control of ligand distribution, both within a tissue and on the cell surface. For example, the clinical features of Simpson-Golabi-Behmel overgrowth syndrome, caused by mutation in the gene encoding Glypican 3, suggest that this protein is involved in regulation of cell survival and/or proliferation. One goal of my laboratory is to identify zebrafish glypicans and characterize developmental processes that they are regulating.

For more information view Dr. Topczewski's faculty profile page

Publications

View Dr. Topczewski's publications at PubMed

Contact

Email Dr. Topczewski

Phone 773-755-6545

Lab Staff

Graduate Students

Rebecca Anderson

The Troyanovsky lab’s research focuses on cadherin, intercellular adhesion and signaling. Classic cadherins are critical proteins mediating cell-cell adhesion and various signaling pathways responsible for cellular proliferation, differentiation and morphogenesis.  Abnormalities in this system are causal factors in many pathologies, including cancer. The molecular mechanisms of cadherin-based adhesion, however, are largely unknown. How do cadherins establish the adhesion contact? How do they interact with the cytoskeleton? What are the signaling pathways they control? Our laboratory's work is centered around these questions. We are currently working on the following specific projects:

• An individual cadherin molecule’s adhesion site is very weak. To mediate tight adhesion, cadherin molecules form clusters. Recently our lab showed that cadherin clustering is based on two different mechanisms. First, using an extracellular cis-binding site, cadherin sticks laterally in small groups. Additional clustering is promoted by the actin cytoskeleton, binding to which limits cadherin diffusion. The aim of our current study is to understand the regulation of cadherin clustering through modulation of the cadherin-actin filament coupling.
• The formation of cadherin adhesive clusters interconnected to the cytoskeleton is not sufficient to establish functional intercellular junctions. The junctions stimulate formation of actin bundles that is required for epithelial cells to organize their actin cytoskeleton. How adherens junctions initiate actin bundle formation is another direction in our research.
• Cadherin is not the only transmembrane protein in adherens junctions. These structures contain adhesion proteins from the nectin family as well as numerous signaling proteins. We showed that one of such proteins, gamma-secretase, interacts with E-cadherin through p120-catenin. The roles of nectins and gamma-secretase and the ways they are recruited into adherens junctions are also areas of focus in our lab.

For more information see Sergey Troyanovsky’s, PhD, faculty profile.

Publications

View Dr. Troyanovsky's publications at PubMed.

Contact

Email Dr. Troyanovsky

Phone the Troyanovsky Lab at 312-503-9275

Lab Staff

Research Associates

Regina Troyanovsky, PhD, Indrajyoti Indra, PhD

Postdoctoral Fellows

Mohammad Abu-Laban, PhD

Our research integrates genetic and genomic approaches with experimental studies using cell-based systems, organ cultures and animal models. In particular, we are studying regulation of fibroblast activation, mesenchymal cell differentiation and the cross-talk between macrophages, monocytes and stromal cells and the role of innate immune signaling, in aberrant tissue remodeling and wound healing.

Fibrosis is a non-specific response that occurs in reaction to any type of chronic or persistent tissue injury. While acute fibrogenesis is beneficial for rapidly restoring tissue homeostasis and regeneration, chronic or deregulated responses to injury lead to scar. Fibrosis is now one of the a leading causes of deaths worldwide. Therefore, an important goal is to define the cells, metabolic states, molecules and signaling pathways that regulate tissue repair and how genetic and epigenetic modifications in these pathways result in chronic fibrosis. We focus on fibrotic diseases affecting the skin, lungs and heart.

We are investigating the molecular mechanisms that control activation of fibroblasts and myofibroblasts and the role of innate immunity, toll-like receptors and related pattern recognition receptors and the cross-talk among monocytes, macrophages, dendritic cells and adipocyte progenitor cells and  mesenchymal stromal cells. In addition, studies are investigating the origins of activated stromal cells, using transgenic lineage tracing approaches. We focus on pathways implicated in large-scale genetic studies are candidates based on their association with scleroderma, pulmonary fibrosis and chronic inflammation.

We routinely employ molecular, cellular, biochemical and genetic approaches in our studies, along with omics approaches such as genomewide transcriptomics and GWAS, proteomics and candidate gene approaches. We make extensive use of human samples such as skin biopsies, lung tissue, explanted fibroblasts and blood cells and animal models of disease. We are also developing organoid approaches to model fibrosis and repair in human skin. Many of our studies focus on the discovery of targeted therapies and of biomarkers for predicting disease severity, activity and response to therapy in genetically diverse human populations.

Publications

View Dr. Varga's publications at PubMed

For more information visit Dr. Varga's faculty profile page

Contact

Contact Dr. Varga at 312-503-8003 or the Varga Lab at 312-503-0498

Research Description

The broad area of our research interest is in the cytoskeleton and intracellular motility. The cytoskeletal polymer that we are most interested in is the microtubules and the cytoskeletal process that we are most excited about is the accurate segregation of chromosomes during mitosis. A dividing cell assembles mitotic kinetochores and a mitotic spindle at the onset of mitosis. The kinetochores serve as sites where the microtubules of the mitotic spindle comes in physical contact with the chromosomes and are hence extremely important for accurate chromosome segregation. Improper kinetochore microtubule (kMT) attachments lead to erroneous chromosome segregation, chromosome loss and aneuploidy in turn, which is the leading cause of cancer in tissue cells and of birth defects and miscarriages during human embryonic development.

Over a decade of research had identified the kinetochore-bound Ndc80 complex as the key requirement for the direct physical contact with microtubules of the spindle. But what is still not understood well is how the kinetochores and the Ndc80 complex remains stably attached to the highly dynamic microtubule plus-ends during mitotic metaphase and subsequent chromosome segregation in anaphase. Work is yeast model system had provided us with important insights into the possible mechanism governing this process, but we still do not have a clear mechanistic picture in vertebrate systems. Work in our lab focusses on understanding the molecular mechanisms that are involved the controlling and regulating kinetochore microtubule attachments in vertebrate cells. We are also very interested to delineate the intricate mechanism that link this event with the activation and silencing of the spindle assembly checkpoint which is also absolutely critical for accurate chromosome segregation

For lab information and more, see Dr. Varma's faculty profile and lab website.

Publications

See Dr. Varma's publications on PubMed.

Contact

Contact Dr. Varma at 312-503-4318 or the lab at 312-503-0824.

Lab Staff

Postdoctoral Fellows

Shivangi Agarwal, Mohammed Amin, Amit Rahi

Graduate Student

Adriana Landeros

Research Description

Dr. Vaughan directs a multidisciplinary research group focused on investigating the role of the plasminogen activator system in cardiovascular disease. Active experimental programs are underway at the molecular and cellular level in animals and in humans. Transgenic and knockout mice are used in a variety of studies designed to explore the tissue-specific expression of PAI-1 in vivo and the role of the fibrinolytic system in vascular disease and tissue remodeling.

For more information visit Dr. Vaughan's faculty profile page.

Publications

View Dr. Vaughan's publications at PubMed.

Contact

Email Dr. Vaughan

Lab Staff

Graduate Students

Varun Nagpal
Rahul Rai

Research Description

Research in our laboratory focuses on two aspects of DNA virus biology:

1) The role of the host translation system during infection by poxviruses. Members of the poxvirus family include Variola Virus (VarV), the causative agent of smallpox, and Vaccinia Virus (VacV), a close relative that was used as a vaccine against smallpox and which has become the laboratory prototype for poxvirus research. These large double-stranded DNA viruses exhibit an impressive level of self-sufficiency and encode many of the proteins required for transcription and replication of their DNA genomes. Indeed, unlike many other DNA viruses, poxviruses do not require access to the host nucleus and replicate exclusively in the cytoplasm of infected cells within compartments termed “viral factories”. However, like all viruses, they remain dependent on gaining access to host ribosomes in order to translate their mRNAs into proteins and must also counteract host antiviral responses aimed at crippling the translation system to prevent virus replication.

Our work focuses on the function of two eukaryotic translation initiation factor (eIF) complexes, eIF3 and eIF4F, that regulate ribosome recruitment to capped mRNAs and their role in VacV infection. We have found that VacV stimulates the assembly of eIF4F complexes and that this is important for both viral protein synthesis and control of host immune responses. Furthermore, we have found that eIF3 functionally communicates with eIF4F during translation initiation and that this plays an important role in VacV replication. We have also found that VacV redistributes key eIF4F subunits to specific regions within viral factories, a process that appears to involve the viral I3 protein.

We are currently exploring the compartmentalized replication of VacV as a means to better understand fundamental mechanisms of localized translational control and how this functions to regulate viral protein synthesis and host antiviral responses. We are also studying how the virus controls eIF4F activity by targeting upstream signaling pathways, with a particular emphasis on the metabolic sensor mammalian target of rapamycin (mTOR).

2) Microtubule regulation and function during herpes simplex virus infection. We are also interested in how herpes simplex virus type 1 (HSV-1) exploits host signaling pathways and specialized microtubule regulatory proteins, called +TIPs, to facilitate virus movement within the cell at various stages of the viral lifecycle.

For lab information and more, see Dr. Walsh's faculty profile and the lab website.

Publications

See publications on PubMed.

Contact

Contact Dr. Walsh at 312-503-4292

Lab Staff

Postdoctoral Fellows

Stephen DiGiuseppe, Charles Hesser, Nathan Meade, Dean Procter

Graduate Students

Colleen Furey, Madeline Rollins

Technical Staff

Research Description

Current Projects

The role of calmodulin (CaM) mediated signal transduction pathways in physiology and pathophysiology

• Using of emerging technologies to understand how CaM and a CaM-regulated enzyme could be encoded, expressed, regulated and assembled into a calcium signal transduction complex
• Using of integrative (in vivo) chemical biology and molecular genetics to gain insight into how landmark CaM-regulated protein kinases are involved in physiology and pathophysiology

Integrative chemical biology and development of novel therapeutics for attenuation of disease progression

• Using the “smart chemistry” approach integrated with “smart biology” screens for rapid discovery of novel small molecules with potential use in targeting pathophysiology progression related to diseases ranging from neurological disorders, cancer, inflammatory conditions, cardiovascular and pulmonary disease
• Discovering and developing novel small molecule compounds that selectively attenuate the increased production of proteins called proinflammatory cytokines, which can cause tissue injury and disease when produced in excess

We ultimately hope to find, by targeting pathophysiology mechanisms which contribute to disease progression, a series of novel small molecules with potential to be effective against a variety of disorders.

For lab information and more, see Dr. Watterson’s faculty profile.

Contact

Contact Dr. Watterson at 312-503-0657.

Lab Staff

Adjunct Professor

Jeff Pelletier

Senior Research Associate

Saktimayee Roy

Postdoctoral Fellows

James Winsor

Research Description

The major area of interest in my laboratory is advancing the state of art in organ regeneration and tissue engineering to develop methods to grow livers and kidneys as a cutting-edge solution to the organ shortage dilemma. Nationally, over 120,000 patients are waiting for solid organ transplantation, yet the number of transplants performed annually falls short of this need by 75%. In the absence of suitable donors for transplantation, organ failure leads to associated health problems, increased healthcare expenditures and death. Organ shortage is a national issue with local impact. In 2010 there were just over 1,050 solitary kidney, liver or heart transplants performed in Illinois, yet 311 patients in the state and more than 6650 nationwide died waiting for an organ.

Our research proposes a multidisciplinary solution to organ shortage by utilizing a tissue engineering approach to rehabilitate the extracellular matrix of organs that are not initially suitable for transplantation. Just-in-time organs, reconstituted with recipient derived progenitor cells, would abrogate the need for long waitlist times and associated waitlist mortality, reduce the reliance on organs from living donors and obviate the need for immunosuppression. Conceptually, these organs would be prepared from a donor matrix using a recipients own cells at the first signs of organ dysfunction. The re-engineered organ would then be ready for implantation when progressive organ failure indicates the need for transplantation. 

The traditional paradigm in tissue engineering has been to grow cells on synthetic, polymer scaffolds to recreate the organ or tissue of interest. The limitation of this approach is the scale-up. Beyond a critical distance, diffusion of nutrients and oxygen is not sufficient to support cellular life and a vascular system must be incorporated into the tissue to supply nutrients. It has been technically difficult to design a synthetic micro-vasculature resembling small, terminal capillaries and to combine these structures with functional cells. Our approach challenges this paradigm by using the natural extracellular matrix as a scaffold to support the growth of new cells capable of repopulating the three-dimensional matrix. We have established protocols to remove parenchyma cells from livers and kidneys with a high efficiency of cellular removal and adequate retention of extracellular matrix molecules. We have further repopulated the vasculature of these matrix structures with endothelial cells derived from induced pluripotent stem cell technology. Together, we have partnered with the McCormick School of Engineering at Northwestern University and other leading academic and industrial centers to advance this fast moving field and address the problem of organ shortage.

For more information, visit the faculty profile of Jason Wertheim, MD/PhD or visit the Wertheim Lab website.

Publications

View publications by Jason Wertheim at PubMed

Contact Us

Dr. Wertheim

Lab Phone 312-695-0257

Research Description

Welcome to the Woodruff Lab, a team of research faculty, post-doctoral professionals, graduate students and lab technicians devoted to the study of ovarian health and development. We are working in three main areas. The first is ovarian follicle development, the study of the formation and maturation of the ovarian follicle, which is the basic functional unit of the ovary. The follicle includes somatic cells (which make hormones like estrogen and inhibin) and the oocyte (or egg). We are attempting to isolate the factors that regulate follicle and oocyte maturation and to understand the mechanisms of follicle and oocyte survival and death. The second focus of the Woodruff Lab is to develop in vitro follicle culture systems that can mimic the normal in vivo patterns of follicle development. The end goal of this research is to allow us to successfully remove healthy ovarian tissue from a cancer patient, safely store it until the patient has completed their treatment and then either harvest follicles from the tissue in an effort to grow them or surgically transplant the tissue to restore natural ovulation. Our third area of study is on the endocrine hormones inhibin and activin, which govern the reproductive cycle. Work on these hormones is essential to an understanding of healthy reproductive cyclicity and on the treatment of infertility.

For lab information and more, see Dr. Teresa Woodruff’s faculty profile and the Woodruff Lab website.

Publications

View publications on PubMed. 

Contact Us

Contact the Woodruff Lab via email.

Lab Staff

Post-doctoral fellows:

Hideyuki Iwahata
Hoi Chang Lee
Jaewang Lee

Research Assistant Professor:

So-Youn Kim

Research Description

RNA Processing and Neurodegeneration

Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.

To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.

A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).

Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis

Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Recent Publications

View a full list of publications by Jane Wu at PubMed

Contact Us

Jane Wu, MD, PhD, at 312-503-0684

Research Description

We broadly investigate the mechanisms used in bacterial cells to regulate antibiotic resistance and gene expression at the translational level. Our long-term goals are to address mechanistic questions about ribosome specialization and resistance evolution, in addition to developing aptamer-based diagnostic tools for bacterial pathogens.

Current Projects

Multidrug resistant ribosome

Macrolides, lincosamides and streptogramins (MLS) are structurally distinct and broad-spectrum antibiotics that inhibit protein biosynthesis by binding to the 50S large subunit of bacterial ribosome.The efficacy of MLS has rapidly eroded due to the widespread dissemination of the Erm RNA methyltransferases that catalyze the transfer of two methyl groups to a conserved adenine nucleotide (m26A2058) in the 23S rRNA of the 50S subunit. This dimethylation sterically hinders the binding of all MLS antibiotics that share the overlapping A2058, in addition to abrogating the MLS resistant bacteria from host immune recognition. Our studies seek to addresses several unresolved questions: How is the expression of erm regulated under antibiotic selection? How does Erm find its target? What are the consequences of ribosome methylation? How do the next-generation antibiotics recognize the methylated ribosome?

Hibernating ribosome

The bacterial 100S ribosome (dimer of 70S complexes) is important for pathogenesis, translational repression, starvation responses, and ribosome turnover. Our goal is to establish a mechanistic understanding of the biogenesis and function of the 100S ribosome in translational silencing and staphylococcal pathogenesis. This project focuses on the following unexplored questions: What factors control the constitutive production of the 100S ribosome in S. aureus? Why are only specific mRNAs translationally repressed during ribosome hibernation? How is hibernation beneficial to ribosome stability? How is ribosome turnover linked to successful host colonization? These questions will be addressed through a multi-disciplinary approach that spans genetics, molecular biophysics, biochemistry, and whole animal infection studies.

For lab information and more, see Dr. Yap's faculty profile.

Publications

See Dr. Yap's publications on PubMed.

Contact

Contact Dr. Yap.

Lab Staff

Postdoctoral Fellows

Anna Lipońska, David Ranava

Research Description

The Zhang laboratory is focused on two research directions: 1) determining role of tumor suppressors in development and cancer progression and 2) identifying immune components that control breast cancer metastasis.

The main focus of my research program is to study the roles of tumor suppressors in normal development and in breast and prostate cancer progression, focusing on maspin and an Ets transcription factor PDEF. Maspin is a unique member of the SERPIN family that plays roles in normal tissue development, tumor metastasis and angiogenesis. Genetic studies by my laboratory using maspin transgenic and knockout mice demonstrated an important role of maspin in normal mammary, prostate and embryonic development. Recently, we have identified several new properties of maspin. As a protein that is present on cell surface, maspin controls cell-ECM adhesion. This function is responsible for maspin-mediated suppression of tumor cell motility and invasion. We have also discovered that maspin is involved in the induction of tumor cell apoptosis through a mitochondrial death pathway. The long-term goals of these projects are to elucidate the molecular mechanisms by which maspin and PDEF control tumor metastasis and to identify their physiological functions in development. These analyses are not only important for basic biology and but also may lead to a therapy for cancer and other developmental diseases.

Another focus of research in Zhang lab is to identify immune components that control breast cancer metastasis. Chronic inflammation not only increases neoplastic transformation but also drives the inhibition of the immune response in a protective negative-feedback mechanism.  Suppressive immune cells are recruited to the sites of inflammation and function to inhibit both innate and adaptive immune responses, enabling tumor tolerance and unmitigated tumor progression. To study the interplay between tumor and immune cells, the Zhang lab has developed a unique animal model of breast cancer that reproduces different stages of breast cancer bone metastasis. Molecules that control tumor-immune cell interaction and immunosuppression have been identified. We are currently studying roles of these genes in tumor-driven evolution that control chronic inflammation and immunosuppression. We hypothesize that these key pro-inflammatory genes are upregulated during cancer progression, which function synergistically to recruit and activate suppressive MDSCs, TAMs and Tregs, inducing chronic inflammation and an immunosuppressive tumor microenvironment conducive to metastatic progression.

For more information visit Ming Zhang's faculty profile.

Publications

View publications by Ming Zhang in PubMed

Contact

Phone 312-503-0449

Research Description

Major research areas in the Zhao lab include:

1. Apoptosis imaging technology development. Programmed cell death (apoptosis) plays a significant role in degenerative diseases. There is currently no clinical tool for assessing apoptosis in pathological conditions. Our research focuses on the development of optimal agents that combine sophisticated binding activities and favorable clearance kinetics for clinical translation.
2. Assessing systemic toxicity in anticancer therapies. The outcome of chemotherapies hinges on the balance between tumor toxicity and patient tolerance. With the ability to noninvasively detect tissue apoptosis, we propose to assess anticancer therapies in a whole-body approach by monitoring tumor cell killing simultaneously with systemic tissue injury in response to chemotherapeutic agents. This is a transformative approach in oncology in terms of optimizing therapies on an individualized basis.
3. Detecting myocardial injury in ischemic heart disease. Non-infarct myocardial injury in ischemic heart disease is of particular interest because this type of cardiac injury is not well understood in terms of its pathophysiological characteristics and its roles in long-term adverse cardiac events. Our research in this area focuses on the diagnosis of non-infarct myocardial injury, which in turn, will help address a significant gap in identifying patients at risk.
4. Investigating the pathogenesis of antiphospholipid syndromes. The presence of circulating antibodies against phosphatidylethanolamine (PE) is positively correlated with clinical manifestations of antiphospholipid syndromes. However, the underlying pathogenic mechanism of anti-PE autoimmunity remains unknown. We have a major interest in investigating the cellular susceptibility to PE-binding agents, which in turn, will shed light on the potential pathogenic mechanism of aPE.

Publications

View publications by Ming Zhao in PubMed.

For more information, visit Dr. Zhao's Faculty Profile page

Contact

Contact Dr. Zhao at 312-503-3226.

Lab Staff

Songwang Hou, PhD
Research Associate

Steven E. Johnson
Graduate Student

Ke Ke, PhD
Research Associate

Kaixi Ren, MD
Graduate Student

Research Description

Recovery of endothelial barrier integrity after vascular injury is vital for endothelial homeostasis and resolution of inflammation. Endothelial dysfunction plays a critical role in the initiation and progression of vascular diseases such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and atherosclerosis. A part of the research in the lab, employing genetically modified mouse models of human diseases, endothelial progenitor cells/stem cells, and translational research approach as well as nanomedicine, is to elucidate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury and determine how aging and epigenetics regulate these processes (J. Clin. Invest. 2006, 116: 2333; J. Exp. Med. 2010, 207:1675; Circulation 2016, 133: 2447).  We are also studying the role of endothelial cells in regulating macrophage functional polarization and resolving inflammatory lung injury. These studies will identify druggable targets leading to novel therapeutic strategies to activate the intrinsic endothelial regeneration program to restore endothelial barrier integrity and reverse edema formation for the prevention and treatment of ARDS in patients.

Pulmonary hypertension is a progressive disease with poor prognosis and high mortality. We are currently investigating the molecular basis underlying the pathogenesis.  We have recently identified the first mouse model of pulmonary arterial hypertension (PAH) with obliterative vascular remodeling including vascular occlusion and formation of plexiform-like lesions resembling the pathology of clinical PAH (Circulation 2016, 133: 2447). Our previous studies also show the critical role of oxidative/nitrative stress in the pathogenesis of PAH as seen in patients (PNAS 2002, 99:11375; J. Clin. Invest. 2009, 119: 2009). With these unique models and lung tissue and cells from idiopathic PAH patients, we will define the molecular and cellular mechanisms underlying severe vascular remodeling and provide novel therapeutic approaches for this devastating disease. 

The Zhao lab employs the state-of-the art technologies including genetic lineage tracing, genetic depletion, genetic reporter, and CRISPR-mediated in vivo genomic editing as well as patient samples to study the molecular mechanisms of acute lung injury/ARDS, and pulmonary hypertension and identify novel therapeutics for these devastating diseases. Current studies include 1) molecular mechanisms of endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis and pneumonia; 2) how aging and epigenetics regulate this process; 3) how endothelial cells regulate macrophage and neuptrophil function for resolution of inflammation and host defense; 4) stem/progenitor cells in acute lung injury and pulmonary hypertension and cell-based therapy; 5) mechanisms of obliterative pulmonary vascular remodeling; 6) molecular basis of right heart failure; 7) pathogenic role of oxidative/nitrative stress; 8) lung regeneration; 9) drug discovery; 10) nanomedicine.

Publications

View publications by Youyang Zhao in PubMed.

For more information, visit Dr. Zhao's Faculty Profile page

Contact

Email Dr. Zhao

Contact Dr. Zhao’s Lab at 773-755-6355

Lab Staff

Zhiyu Dai, PhD.
Research Assistant Professor

Xianming Zhang, PhD.
Research Assistant Professor

Narsa Machireddy, PhD.
Research Assistant Professor

Junjie Xing, PhD.
Research Scientist

Colin Evans, PhD.
Research Scientist

Varsha Suresh Kumar, PhD.
Research Scientist

Xiaojia Huang, PhD
Research Scientist

Hua Jin, PhD
Postdoctoral fellow

Yi Peng, PhD
Research Scientist

Mengqi Zhu, M.S.,
Graduate Student

Left: Three rows of outer hair cells showing prestin proteins (green). Right: location of marshalin (green) in the organ of Corti, the mammalian hearing organ. Microtubule bundles (red) are stained with anti-a-tubulin.

Research Description

The goal of my lab is to identify and investigate molecules that play important roles in mammalian hearing, thus enriching our understanding of cochlear physiology and further developing a better strategy to prevent hearing loss. Deafness is commonly caused by defects in inner ear hair cells. In mammalian cochleae, inner hair cells (IHCs) function as sensory receptors conveying sound-related information to the central nervous system. Outer hair cells (OHCs) amplify the mechanical signals delivered to IHCs. The cooperation between IHCs and OHCs results in sensitive hearing and sharp tuning. Complex and sophisticated protein networks in hair cells facilitate their functions. Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. Our research has been centered on several important proteins expressed in cochlea.

1. Molecular basis of cochlear amplification. OHCs undergo rapid somatic length changes when the voltage across their membrane is altered. This unique somatic electromotility provides the local mechanical amplification of the cochlear response to sound. Without OHCs, hearing threshold is elevated by 40-50 dB and frequency resolution deteriorates. Prestin is the motor protein of OHCs and is required for cochlear amplification (Zheng et al., Nature, 2000). Coincidently, prestin is only expressed in OHCs, which are also the most vulnerable cells in the organ of Corti. In the past, studying OHC amplification mechanisms and preventing OHC loss were considered two separate research fields. However, our recent data indicate a close connection between prestin's function and the vulnerability of OHCs to a variety of ototoxic exposures. To understand this link, we focus on investigating the molecular mechanism of the motor protein prestin using various cellular, biochemical and molecular biological methods.

2. Protein network of hair cells. We are focus on several deafness-related proteins: CDH23, CEACAM16 and Marshalin. Cadherin 23 is a tip-link protein of hair cells. CEACAM16 is an adhesive protein localized at the tectorial membrane (Zheng et al. PNAS, 2011). Marshalin is another newly identified microtubule minus-end binding protein that is expressed in the inner ear. Its expression is developmentally controlled (Zheng et al., Biology Open 2013). Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. We are in the process of investigating interactions among these proteins and their physiological roles for normal hearing and deafness.

For more information, visit the faculty profile of Jing Zheng, PhD.

Publications

View Dr. Zheng's publications in PubMed

Contact

Phone 312-503-3417

Lab Staff

Research Associate

Satoe Humma

Research Technician

Vincent Mui