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Physiologic Systems

Research into the development, physiologic functions and diseases of physiologic systems.

All Labs in This Area

 Sarki Abdulkadir Lab

Studying the mechanisms of prostate cancer initiation, progression and recurrence and strategies to therapeutically target these processes

Research Description

Our laboratory focuses on understanding the molecular mechanisms that drive prostate cancer initiation, progression and recurrence with the ultimate goal of developing therapeutic strategies that target these processes. Our approach includes the genomic analysis of human tumors, cell culture studies and the use of genetically engineered mouse models. We have a strong interest in genomics and gene regulation, oncogenic kinases as potential molecular therapeutic targets and the use of in vivo lineage tracing to define the fates of specific cell populations in tumorigenesis.

Specific projects include:

The role of the oncogenic serine/threonine kinase PIM1 in prostate cancer - PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia, radiation and treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia/radiation/docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore, PIM1 may represent a valuable therapeutic target in prostate cancer. We are using new mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We are investigating how PIM1 promotes prostate tumorigenesis by phosphorylating these substrates involved in regulating MYC transcriptional activity and stem cell function.

Cellular and molecular determinants of prostate cancer recurrence - A major clinical problem in prostate cancer is that of tumor recurrence following initial apparently successful therapy. Recurrent tumors may arise from a small number of "cancer stem-like cells" that survive the initial therapeutic intervention and have the capacity to regenerate the tumor. We are using lineage tracing to examine the competence of specific prostate epithelial cell types to regenerate tumors following therapy in mice.

Targeting lethal prostate cancer – We are using our mouse model of lethal prostate cancer based on alterations in Myc, Pten and Tp53 to develop new targeted therapies. One current project involves the targeting of EphB4 receptor tyrosine kinase using an antagonist as a therapeutic strategy.

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

Publications

Rodríguez Y, Unno K, Truica MI, Chalmers ZR, Yoo YA, Vatapalli R, Sagar V, Yu J, Lysy B, Hussain M, Han H, Abdulkadir SA. A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2022 Jun 6;82(11):2110-2123.

Chalmers ZR, Burns MC, Ebot EM, Frampton GM, Ross JS, Hussain MHA, Abdulkadir SA. Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2-ERG fusions. Prostate Cancer Prostatic Dis. 2021 Jun;24(2):558-566.

Unno K, Chalmers ZR, Pamarthy S, Vatapalli R, Rodriguez Y, Lysy B, Mok H, Sagar V, Han H, Yoo YA, Ku SY, Beltran H, Zhao Y, Abdulkadir SA. Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer. Cancer Res. 2021 Apr 15;81(8):2157-2170.

Sagar V, Vatapalli R, Lysy B, Pamarthy S, Anker JF, Rodriguez Y, Han H, Unno K, Stadler WM, Catalona WJ, Hussain M, Gill PS, Abdulkadir SA. EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells. Cell Death and Disease. November 2019.

Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I, Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell.  November 2019.

Njoroge RN, Vatapalli RJ, Abdulkadir SA. Organoids increase the predictive value of in vitro cancer chemoprevention studies for in vivo outcome. Frontiers in Oncology. January 2019.

See Dr. Abdulkadir's publications in PubMed.

Contact Us

Dr. Abdulkadir
Lab Telephone: 312-503-5031

 Hossein Ardehali Lab

Role of mitochondria and metabolic processes in cancer growth, cardiac disease and immunological processes

 

Research Description

Our lab focuses on three major areas of research:

Role of hexokinase enzymes in immune function, cancer growth and stem cell differentiation

Hexokinase (HK) enzymes phosphorylate glucose to trap it inside the cell. There are 5 mammalian HKs (named HK1-5), with two of them having a hydrophobic region at their N-terminus that allows them to bind to the mitochondria. We have made mouse models and developed in vitro systems to allow us to study the role of mitochondrial binding of HKs in glucose metabolism. We have determined that HK1 binding to the mitochondria determines whether glucose is used for anabolic processes (ie, pentose-phosphate pathway) or catabolism (ie, glycolysis). Thus, the non-enzymatic function of this protein and its subcellular location determines the fate of glucose. We are now studying this process in T-cells, vascular cells and cancer cells. We are also in the process of generating several mouse models of hexokinase enzymes, including HK2 without the mitochondrial binding domain and HK3 knockout mice. We will study these models in different disease and physiological conditions.

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 through epigenetic changes, 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.

Role of mRNA-binding proteins 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.

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

Publications

See Dr. Ardehali's publications in PubMed.

Contact

Dr. Ardehali

 Rishi Arora Lab

Understanding the molecular and signaling pathways involved in atrial fibrillation.

 

The primary focus of the Arora lab is to obtain a better understanding of the molecular mechanisms underlying heart rhythm disorders (cardiac arrhythmias). The cardiac arrhythmia most closely studied in the Arora lab is atrial fibrillation (AF). AF is the most common rhythm disorder of the heart that affects >6 million American and is a major cause of stroke. Unfortunately, current therapies for AF have suboptimal efficacy. This is thought to be because current therapies are not targeted at the major molecular mechanisms underlying AF. The focus of research in the Arora lab has therefore been to not only better understand the molecular mechanisms underlying AF but to discover new, mechanism-guided therapies for this condition. Dr. Arora’s laboratory is one of the few in the world dedicated to understanding the molecular mechanisms underlying AF and to translating these research findings to the clinic.

Over the last 15 years, the Arora lab has discovered that autonomic nervous system signaling, oxidative injury, altered excitation-contraction coupling and TGF-β signaling are key mechanisms underlying the genesis of AF. Because AF is predominantly a disorder of the larger, mammalian heart, the Arora lab laboratory primarily uses large animal models of AF to understand mechanisms of AF. Over the last few years, the Arora lab has developed new gene-based therapies for this condition. This has included not only the gene-based targeting of key molecular signaling pathways underlying AF, but has also included the development of new devices and energy sources (such as electroporation) to perform targeted gene delivery in the heart.

In its quest to develop new, mechanism guided therapies for AF, the Arora lab is also engaged in the development of new, signal processing algorithms to study the electrical signals (electrograms) in the fibrillating heart. Over the last several years, the lab have published many papers on how AF electrograms can be used to determine pathophysiological substrate for AF.

Dr. Arora has mentored more than 40 trainees in his lab over the last 17 years, and currently serve as training director on a major grant from the American Heart Association. The lab is an ideal home for graduate students interesting in the following areas of biology:

Cardiovascular physiology, with a focus on cardiac electrophysiology: The lab uses a variety of cutting edge techniques to study the electrophysiology of the heart from cell-to-bedside. This includes high resolution electrophysiological mapping in the intact heart (in-vivo), high resolution optical mapping in the explanted heart (ex-vivo) and cellular electrophysiological techniques in isolated cardiomyocytes to assess excitation contraction coupling (calcium cycling) and whole cell ion channel electrophysiology. Biomedical engineering, instrumentation: The lab uses a variety of signal processing techniques to assess intracardiac electrograms from animals and humans with AF. The lab also investigates the behavior of autonomic nerves in the heart, using digital signal processing. In addition to signal processing, the lab is also actively engaged in the development of new devices (hardware) to perform gene delivery in the heart.

Gene therapy: A major focus of the lab is to develop new gene therapy approaches for cardiac arrhythmias. This includes the identification of novel gene targets in AF, use of new delivery vectors (non-viral and viral) for targeted gene therapy in the heart, and the development of new, catheter-based gene delivery techniques.

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

Publications

See Dr. Arora's publications in PubMed.

 Kelly Bachta Lab

Antimicrobial resistance mechanisms and pathogenesis of clinically-important bacterial pathogens including Pseudomonas aeruginosa and Enterococcus faecium

Research Description

 The Bachta laboratory has two main research foci:
  1. We investigate the pathogenesis of Pseudomonas aeruginosa infections using imaging and sequencing techniques to define infection dynamics during the context of infection. P. aeruginosa is a gram-negative bacterium that commonly infects immunocompromised hosts.  Recently, observations revealed that P. aeruginosa traffics to the gallbladder where it rapidly replicates.  Current projects seek to uncover novel genetic elements required for replication in the gallbladder and understand the role that this organ plays in disease outcome and bacterial transmission.
  2. We investigate the development of multidrug resistance phenotypes in clinically relevant pathogens including Pseudomonas aeruginosa and Enterococcus faecium.  We are currently exploring novel pathways involved in colistin resistance in P. aeruginosa and characterizing novel mutations in beta-lactamases that lead to antimicrobial resistance.  Finally, we’ve begun a collaboration with the NMH clinical microbiology laboratory to apply whole-genome sequencing and molecular epidemiology to track outbreaks of vancomycin-resistant Enterococcus in the hospital. 

Overall, our studies utilize a broad range of techniques including animal modeling, molecular and biochemical techniques, bacterial whole genome sequencing and antimicrobial resistance testing to explore bacterial pathogenesis and antimicrobial resistance.  We hope that these basic insights will lead to improved diagnostics and therapeutics for bacterial diseases.  

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

Publications

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

Contact Us

Kelly Bachta, MD, PhD at 312-503-3354

 

 Grant Barish Lab

Transcriptional regulators of inflammation and metabolism

Research Description

The burgeoning epidemic of obesity and type 2 diabetes mellitus presents a major health and therapeutic challenge.  Transcriptional regulation is the fundamental control mechanism for metabolism, but a gap remains in our knowledge of gene regulatory pathways that control lipid and glucose homeostasis.  Thus, we seek to identify modulable pathways that may be leveraged to counteract diabetes mellitus and its comorbidities, particularly cardiovascular disease.  In this effort, we use a variety of genetic, molecular, next-generation sequencing, biochemical methods and physiological models.  Our recent work has helped to reveal the genomic architecture for transcriptional regulation in innate immunity, which plays a key role in both diabetes mellitus and atherosclerosis.  Surprisingly, although macrophage regulatory elements are often at significant linear distance from their associated genes, we identified interplay between transcriptional activators and repressors that is highly proximate, occurring at shared nucleosomal domains (Genes & Development, 2010).  Moreover, we discovered a powerful role for the BCL6 transcriptional repressor to maintain macrophage quiescence and prevent atherosclerosis (Cell Metabolism, 2012). 

Currently, we are exploring the impact of activator–repressor interactions on enhancer function and transcription, the signal-dependent control of repression and the functional impact of transcriptional activators and repressors on inflammatory and metabolic disease. In particular, we strive to further understand the role for B cell lymphoma 6 (BCL6), a C2H2-type zinc finger repressor, in innate immunity and metabolism. 

In related work, we are developing new methods for cell-specific isolation of RNA and chromatin from tissues composed of mixed cell populations. These genetic tools will allow us to explore transcriptional regulation in living animals with unprecedented precision and global scope using transcriptome sequencing and ChIP-sequencing. We anticipate that these approaches will identify new candidate regulators and mechanisms underlying cardiovascular and metabolic disease. 

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

Publications

See Dr. Barish's publications in PubMed.

Graduate Students

Madhavi Senagolage
Meredith Chase
Krithika Ramachandran

Contact

Dr. Barish

 Joseph Bass Lab

Circadian and metabolic gene networks in the development of diabetes and obesity

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

 Daniel Batlle Lab

Focusing on the renin angiotensin system as it relates to the understanding of human diabetic kidney disease and rodent models of diabetic kidney disease and hypertension

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

 Issam Ben-Sahra Lab

Decoding connections between signaling and metabolic networks

Research Description

The Ben-Sahra lab seeks to identify novel connections between oncogenic and physiological signals and cellular metabolism. My previous studies revealed new connections between mTORC1 (mechanistic Target of Rapamycin Complex I) signaling and de novo nucleotide synthesis pathways.

Using isotopic tracing experiments and genetic approaches, my lab investigates whether the additional signaling pathways such as PI3K/Akt, RAF/Erk, Hippo/Yap or AMPK could regulate metabolic pathways that supply small metabolites to sustain nucleotide synthesis independently of mTORC1 signaling. Furthermore, we are also interested in understanding how cells can sense changes in nucleotide levels. In addition to nucleotide metabolism, we also study connections between signaling pathway and global cancer cell metabolism. I predict that there could be points of regulations which could give selective advantages to cancer cells to grow and proliferate. The initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century.

Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as a critical factor in determining therapeutic targets that yield greatest drug efficacy with marginal harmful effect on normal cells. Our research will enable further progress in the exploitation of unusual metabolic features in cancer as a means of therapeutic intervention.

For lab information and more, see Dr. Ben-Sahra's faculty profile and lab website.

Publications

See Dr. Ben-Sahra's publications on PubMed.

Contact

Contact Dr. Ben-Sahra.

 Lisa Beutler Lab

Dissecting the mechanisms of gut-brain communication underlying energy homeostasis

Research Description

Our goal is to understand how the gut and the brain communicate with each other to maintain body weight, and how this goes awry in diseases such as obesity. To accomplish this, we use a variety of techniques including optogenetics and calcium imaging in genetically modified mice. Projects in the lab focus both on how information about nutrients in the gastrointestinal tract are transmitted to the brain and how the brain regulates gastrointestinal tract function to optimize digestion and metabolism.

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

Publications

See Dr. Beutler's publications in PubMed.

Contact

Dr. Beutler

 G.R. Scott Budinger Lab

Mechanisms of aging and proteostasis stress

Research Description

The Budinger lab studies the mechanisms underlying the loss of organismal resilience during aging, focusing on the hypothesis that some of these changes are induced by chronic stress to the proteostasis network.  We are particularly interested in how proteostasis stress during aging induces dysfunction in tissue resident macrophages in the lung, brain and skeletal muscle that are important for organ repair.  We use pneumonia as a model of systemic organismal stress in animals that mimics many of the features we see in patients hospitalized for pneumonia in our hospital.

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

Publications

See Dr. Budinger's publications on PubMed.

Contact

Contact Dr. Budinger or the administrative office at 312-908-7737.

 

 Serdar Bulun Lab

Estrogen metabolism in breast cancer, endometriosis and uterine fibroids.

Research Description

The laboratory research of Serdar E. Bulun, MD, focuses on studying estrogen biosynthesis and metabolism, in particular aromatase expression, in hormone-dependent human diseases such as breast cancer, endometriosis and uterine fibroids.

A team of investigators works on understanding the epithelial-stromal interactions and aromatase overexpression in breast cancer tissue. Because aromatase inhibitors treat breast tumors primarily via suppressing intratumoral estrogen biosynthesis, these efforts are important for discovering new targets of treatment.

Another team studies endometriosis. Basic data from this laboratory led to the introduction of aromatase inhibitors into endometriosis treatment. Human tissues and a primate model are used to elucidate cellular and molecular mechanisms responsible for the development of endometriosis.

Regulation of aromatase expression is also studied in uterine fibroids, benign tumors that are dependent on estrogen for growth, by a third team. 

A fourth team is investigating the link between progesterone action and estrogen inactivation in normal endometrium and endometriosis.

Lastly, a fifth team has identified novel mutations that cause familial excessive estrogen formation syndrome. This syndrome is characterized by short stature, gynecomastia and hypogonadism in males and early breast development and irregular menses in females. In this syndrome, heterozygous inversions in chromosome 15q21, which cause the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in estrogen excess owing to the overexpression of aromatase in many tissues.

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

Publications

See Dr. Bulun's publications in PubMed.

Contact

Dr. Bulun

 Paul Burridge Lab

Investigating the application of human induced pluripotent stem cells to study the pharmacogenomics of chemotherapy off-target toxicity and efficacy

Research Description

The Burridge lab studies the role of the genome in influencing drug responses, known as pharmacogenomics or personalized medicine. Our major model is human induced pluripotent stem cells (hiPSC), generated from patient's blood or skin. We use a combination of next generation sequencing, automation and robotics, high-throughput drug screening, high-content imaging, tissue engineering, electrophysiological and physiological testing to better understand the mechanisms of drug response and action.

Our major effort has been related to patient-specific responses to chemotherapy agents. We ask the question: what is the genetic reason why some patients have a minimal side effects to their cancer treatment, whilst others have encounter highly detrimental side-effects? These side-effects  can include cardiomyopathy (heart failure or arrhythmias), peripheral neuropathy,  or hepatotoxicity (liver failure). It is our aim to add to risk-based screening by functionally validating genetic changes that predispose a patient to a specific drug response.

Recent Findings

  • Human induced pluripotent stem cells predict breast cancer patients’ predilection to doxorubicin-induced cardiotoxicity
  • Chemically defined generation of human cardiomyocytes

Current Projects

  • Modeling the role of the genome in doxorubicin-induced cardiotoxicity using hiPSC
  • Investigating the pharmacogenomics of tyrosine kinase inhibitor cardiotoxicity
  • hiPSC reprogramming, culture and differentiation techniques
  • High-throughput and high-content methodologies in hiPSC-based screening

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

Publications

See Dr. Burridge's publications on PubMed.

Contact

Contact Dr. Burridge at 312-503-4895.

Lab Staff

Postdoctoral Fellows

Malorie Blancard, Hananeh Fonoudi, Mariam Jouni, Davi Leite, Tarek Mohamed, Disheet Shah

Graduate Students

Liora Altman-Sagan, Raymond Copley, K. Ashley Fetterman, Phillip Freeman, Donald McKenna, Emily Pinheiro, Marisol Tejeda, Carly Weddle

Technical Staff

Ali Negahi Shirazi

 Debabrata Chakravarti Lab

Epigenome and 3D chromatin organization dysregulations define human cancers and reproductive diseases

Research Description

Dr. Chakravarti’s research is focused on understanding epigenetic and transcriptional regulation of human tumorigenesis.  One of his research projects is focused on understanding the mechanisms that drive the development of uterine fibroids and endometriosis that affect an alarmingly high number of all women.  In another project, Dr. Chakravarti’s research team investigates molecular underpinning of contribution of transcription factors, cofactors and epigenomic and 3D genome reorganization regulation of prostate Cancer that affects a large number of men worldwide.  In a third project the laboratory determines the role of protein cofactors in regulation of cell cycle genes. Thus, our work interfaces both fundamental and translational research on diseases that affect humankind.  It is our hope that when combined with results from others, our research will contribute to the development of future therapeutics.  Dr. Chakravarti gratefully acknowledges continuous funding support from the NIH and key roles of his lab members and collaborators in the overall success of the Chakravarti Laboratory.

Dr. Chakravarti also enjoys teaching.  He has continuously taught both medical and graduate students.  He serves on numerous Ph.D thesis committees.  He has trained a large number of graduate students and postdoctoral fellows some of whom are now independent investigators at this and other institutions.

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

Publications

See Dr. Chakravarti's publications in PubMed.
Associate Editor: Endocrinology 2017-present; Editorial Board:  Molecular Endocrinology 2011- present, Mol. Cell. Biol. 2014-present
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

Contact Us

Dr. Chakravarti

312-503-1641

 Cheng Lab

Dr. Cheng’s lab investigates cancer stem cell biology, cellular signaling and therapy responses in human brain tumors, particularly glioblastoma (GBM).

Research Description

Our lab broadly studies cancer stem cell biology, cellular signaling, RNA biology, and therapy responses in human brain tumors, in particular, glioblastoma (GBM). We have a range of different projects currently underway in glioma cell lines, gliomas stem-like cells (GSCs), patient-derived xenograft (PDX) GBM model, human iPSC-derived glioma organoid model, orthotopic glioma xenograft model in mice, and clinical glioma tumor specimens. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, and therapy responses of GSCs and GBMs.

Roles of RNA alternative splicing and RNA-binding proteins in glioma

RNA alternative splicing (AS), an evolutionarily conserved co-transcriptional process, is an important and influential determinant of transcriptome and proteome landscapes in normal and disease states such as cancer. AS is regulated by a group of RNA binding proteins (RBPs) that bind to the cis-acting elements in proximity to a splice site thus affecting spliceosome assembly. In cancers, altered expression of or mutations in RBPs result in dysregulated AS that impacts cancer biologic properties. We have established AS/RBP networks that are dysregulated in both adult and pediatric gliomas through bioinformatic analysis of both public and our own datasets of clinical glioma tumors. We are investigating the biological significance of AS/RBPs dysregulation in glioma progression and therapy response by using human iPSC-derived glioma organoid model and GSC brain xenograft models in animals. In addition, we are exploring novel therapeutic approaches of targeting glioma-associated AS/RBP networks to treat GBMs.

Roles of Non-coding RNAs in glioma 

Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms.  Dysregulated ncRNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of lncRNAs or circRNAs influence GBM malignant phenotypes through interactions with signaling pathways. We study the molecular consequences and explore clinical applications of modulating ncRNAs and related oncogenic signaling pathways in GBM.  We are establishing profiles of ncRNAs in clinical gliomas and patient-derived GSCs, and study mechanisms and biological influences of these ncRNAs in regulating GSC biology and GBM phenotypes. 

Aberrant DNA and RNA structures in therapy-resistant GBM

Standard of care treatment for GBM includes the DNA damaging agent temozolomide (TMZ), which has a known mechanism of action to target and mutate guanine bases. With this knowledge in hand, we sought to determine the effects of guanine (G) mutations in DNA and RNA secondary structure. G’s are important for creating structures like g-quadruplexes in both DNA and RNA which can affect changes in translation or be used as docking sites for DNA repair and RNA binding proteins. Using whole genome sequencing data along with isogenic drug sensitive and resistant lines, we are investigating the role of G mutations in DNA and RNA secondary structure to determine potential therapeutic avenues with the help of a chemical biologist to create novel drugs to target these TMZ-induced aberrant pathways.

Targeting autophagy to treat glioma

Autophagy is an evolutionarily conserved process that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism, thus serving as a protective mechanism against stressors and diverse pathologies including cancer. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy-related 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 in autophagy-related proteins inhibits autophagy and enhances the efficacy of combination therapies in GBMs. In collaboration with a medicinal chemist, we are characterizing a next generation of novel autophagy inhibitors that specifically target a key autophagy regulator that we recently reported.

Multi-omics and GBM non-responsiveness to immunotherapies

GBM is categorized as a “cold” tumor that does not respond to current immunotherapies using various immune-checkpoint blockers. Although extensive efforts have been made to sensitize GBM to immunotherapies, the mechanistic studies to determine alternative therapies from understanding the underlying signaling and clinical trial results are still disappointing. We are interested in utilizing the information of multi-omics of clinical gliomas, in particular, proteomics profiling in relation to genomic and epigenomic profiling, to identify potential protein targets that could be the major modulators through post-translational modifications in these “cold” GBM tumors. We will also consider the involvement of tumor microenvironment and immune cells in these conditions. These studies are a brand-new direction that are high-risk and high-reward to turn “cold” GBM tumors to immunotherapy responsive tumors.

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.

 

 Nicolae Valentin David Lab

Molecular mechanisms of metabolic bone diseases, with particular emphasis on the regulation and function of FGF23 in situations of normal and abnormal mineral metabolism.

Dr. David uses a basic science and translational research approach to characterize molecular events that are involved in the expression, post-translational modifications and secretion of the bone hormone FGF23 that is highly elevated in patients with chronic kidney disease (CKD). A major area of his research focuses on investigating a novel mechanism by which inflammatory signals and iron deficiency, common consequences of CKD, regulate FGF23. Our data show that acute inflammation stimulates FGF23 production, but simultaneous increases in FGF23 cleavage maintain normal levels of biologically active protein. However, chronic inflammation and sustained iron deficiency also increase biologically active FGF23, and show that these factors may contribute to elevated FGF23 levels in CKD.

Dr. David’s laboratory is funded by the National Institute of Health, National Institute of Diabetes and the National institute of Digestive and Kidney Diseases (NIDDK).

Email Dr. David

Faculty Profile

Nicolae Valentin David, PhD

 Francesca Duncan Lab

Mammalian ovarian and gamete biology and reproductive aging

Research Description

Aging is associated with cellular and tissue deterioration and is a prime risk factor for chronic
diseases and declining health. The female reproductive system is the first to age in humans, with
a decline in egg quantity and quality beginning at ~35 years of age and menopause ensuing at
~50 years of age. Female reproductive aging has significant health consequences as it results in
endocrine function loss and is a leading cause of infertility, miscarriages, and birth defects.
Although aging hallmarks and mechanisms have been enumerated across multiple organ
systems and species, they have not been investigated in the context of mammalian reproductive
aging.

My research program integrates and builds upon my 18-year history in the field of reproductive
science and medicine to investigate the overarching hypothesis that deterioration of oocyte-intrinsic
cellular pathways together with alterations in the ovarian environment underlie the age-associated
decline in female gamete quantity and quality. Our work is at the interface of
reproductive aging and systemic aging; physiologic and iatrogenic reproductive aging; gamete,
follicle, and ovarian biology; and reproductive science and medicine. Our comprehensive insights
will help us design targeted interventions to potentially slow or counteract reproductive aging,
laying the foundation to simultaneously improve women’s fertile-span and health-span across
generations. In addition, reproductive aging mechanisms may inform those that precipitate
general aging, which occur up to decades later in life. Moreover, the mechanisms involved in
reproductive aging that we are investigating - aneuploidy, protein metabolism dysregulation,
and fibrosis and inflammation – are also central to other conditions such as cancer
pathogenesis. Thus, our research has broad impact and collaborative opportunities across
disciplines, which already include biochemistry, biophysics, toxicology and pharmacology, and
reproductive endocrinology and infertility.


Ultimately our work in reproductive aging will have direct impacts on public health in two ways.
First, reproductive aging affects all women, and menopause and premature aging of the ovary
accelerates aging in general. Such health consequences occur because ovarian hormones such
as estrogen, for example, are critical for cardiovascular, bone, immune, and cognitive functions.
Second, reproductive aging is associated with age-associated infertility, which has significant
societal, clinical, and health ramifications as more women globally are delaying childbearing.

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

Visit the Duncan Lab website

Publications

See Dr. Duncan's publications on PubMed.

Contact

Email Dr. Duncan

312-503-2172

 Lillian Eichner Lab

Transcriptional dependencies in cancer at the intersection of epigenetics, signaling and metabolism

Research Description

The Eichner lab studies transcriptional dependencies in cancer development, progression and resistance mechanisms. We endeavor to elucidate in vivo transcriptional dependencies at the intersection of epigenetics, signaling, and metabolism to reveal and harness therapeutically targetable transcriptional vulnerabilities in cancer.

Project 1

LKB1 (STK11) is among the most frequently mutated genes in Non-Small Cell Lung Cancer (NSCLC), where it is inactivated in about 20 percent of cases. Leveraging immune-competent genetically engineered mouse models to answer key questions in vivo, our work has revealed key insights into the molecular mechanisms driving this disease. We have identified that transcription plays an important and previously underappreciated role in mediating LKB1 function. Future work will continue utilizing mechanistic understanding to explore novel in vivo transcriptional dependencies and therapeutic liabilities of LKB1 mutant tumors.

Project 2

We have identified critical roles of the druggable epigenetic regulator Histone Deacetylase 3 (HDAC3) in lung tumors. We found that HDAC3 directly represses the secretory component of the cellular senescence program, the SASP, and restrains recruitment of T-cells into tumors in vivo. Future work will continue defining the molecular mechanisms mediating HDAC3’s contribution to tumorigenesis, and further explore epigenetic regulation of the senescence program.

For lab information, publications and more, see Dr. Eichner's faculty profile and laboratory website.

Publications

See Dr. Eichner's publications on PubMed.

Contact

Contact Dr. Eichner.

 Matthew Feinstein Lab

Adaptive Immune Response and Regulation in Cardiovascular Diseases 

Research Description

Our lab focuses on clinical and translational immunocardiology. The central approach we use is one of reverse translation: This enables us to take insights from human phenotypes and models of disease, test and refine these insights and hypotheses in experimental models, and ultimately bring these insights to clinic. Leveraging our expertise in clinical and epidemiological research as well as translational and basic investigation, we utilize techniques including single-cell RNA-seq, spatial sequencing (in myocardial and vascular tissue), cutting edge tissue visualization techniques, and traditional immune phenotyping methods (e.g. flow cytometry) to probe the immunopathogenesis of specific cardiovascular diseases (CVDs). To support our investigation of these tissue- and disease-specific processes, we have linked complex individual-level clinical data to stored FFPE tissue specimens from >2000 patients who underwent autopsy, enabling interrogation of multi-organ interactions in the immunopathogenesis of CVDs. We developed the first model of closed-chest ischemia-reperfusion injury in nonhuman primates and use this to interrogate local and peripheral immune responses to myocardial ischemia and infarction in immune-competent and immune-dysregulated models. After we generate target- and tissue-specific hypotheses in human and large animal models, our close collaboration with the Thorp Lab through our shared Clinical and Translational Immunocardiology Program (sites.northwestern.edu/ctip) enables us to experimentally probe processes of interest in small animal and in-vitro models, then ultimately bring these insights and potential therapies to NHP models and back to humans.   

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

Publications

View Dr. Feinstein's full list of publications on PubMed.

Contact Us

Matthew Feinstein, MD 

 

 Al George Lab

Investigating the structure, function, pharmacology and molecular genetics of ion channels and channelopathies

George Lab

Research Description

Ion channels are ubiquitous membrane proteins that serve a variety of important physiological functions, provide targets for many types of pharmacological agents and are encoded by genes that can be the basis for inherited diseases affecting the heart, skeletal muscle and nervous system.

Dr. George's research program is focused on the structure, function, pharmacology and molecular genetics of ion channels. He is an internationally recognized leader in the field of channelopathies based on his important discoveries on inherited muscle disorders (periodic paralysis, myotonia), inherited cardiac arrhythmias (congenital long-QT syndrome) and genetic epilepsies. Dr. George’s laboratory was first to determine the functional consequences of a human cardiac sodium channel mutation associated with an inherited cardiac arrhythmia. His group has elucidated the functional and molecular consequences of several brain sodium channel mutations that cause various familial epilepsies and an inherited form of migraine. These finding have motivated pharmacological studies designed to find compounds that suppress aberrant functional behaviors caused by mutations.

Recent Findings

  • Discovery of novel, de novo mutations in human calmodulin genes responsible for early onset, life threatening cardiac arrhythmias in infants and elucidation of the biochemical and physiological consequences of the mutations.
  • Demonstration that a novel sodium channel blocker capable of preferential inhibition of persistent sodium current has potent antiepileptic effects.
  • Elucidation of the biophysical mechanism responsible for G-protein activation of a human voltage-gated sodium channel (NaV1.9) involved in pain perception.

Current Projects

  • Investigating the functional and physiological consequences of human voltage-gated sodium channel mutations responsible for either congenital cardiac arrhythmias or epilepsy.
  • Evaluating the efficacy and pharmacology of novel sodium channel blockers in mouse models of human genetic epilepsies.
  • Implementing high throughput technologies for studying genetic variability in drug metabolism.
  • Implementing automated electrophysiology as a screening platform for ion channels.

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

Publications

See Dr. George's publications on PubMed.

Contact

Contact Dr. George at 312-503-4892.

Lab Staff

Research Faculty

Irawati Kandela, Thomas Lukas, Christopher Thompson, Carlos Vanoye

Senior Researchers

Reshma Desai, Jean-Marc DekeyserPaula FriedmanChristine Simmons

Lab Manager

Tatiana Abramova

Postdoctoral Fellows

Dina Simkin

Medical Residents

Scott Adney, Tracy Gertler

Graduate Students

Huey Dalton, Surobhi Ganguly, Adil WafaLisa Wren

Technical Staff

Nora Ghabra, Nirvani Jairam

 Jeffrey Goldstein Lab

Placental diagnosis and deep phenotyping using machine learning and artificial intelligence.

Research Description

Area: Placenta diagnosis and deep phenotyping by machine learning:
Diagnosis of placental abnormalities relies on microscopic examination of glass slides. Digitizing the slides to form whole slide images opens several avenues for applying machine learning techniques. Avenues of research include studies to improve interobserver reliability, decrease vulnerability to artifacts, aid humans in diagnosing, and produce explainable predictions. Machine learning techniques can be used to probe basic problems in placental biology and pathophysiology, quantifying changes that evade routine human detection.
Area: Placental diagnosis using AI on placental photographs:
 Placental examination can provide insight into future maternal and child health, but preparation of slides and expert examination are expensive and time consuming. Many diagnoses can be made in whole or in part from the photographic appearance of the placentas. An AI algorithm, installed on smart phones, could make placental examination feasible for all births, everywhere. Bioinformatic studies of electronic health records can identify new associations between placental features and outcomes.

For lab information and more, see Jeffrey Goldstein, MD,PhD, faculty profile.

Publications

See Dr. Goldstein's publications

Contact

Email Dr. Goldstein

 

 Cara Gottardi Lab

The Gottardi Lab investigates how cells adhere to each other and how this adhesion is regulated and controls gene expression in heath and disease.

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

 

 Richard Green Lab

The Green Lab investigates the genetics and molecular biology of cholestatic liver diseases and fatty liver disorders. The major current focus is on the role of ER Stress and the Unfolded Protein Response (UPR) in the pathogenesis of these hepatic diseases.

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

 SeungHye Han Lab

Mitochondrial metabolism and lung stem cells in lung injury and repair

Research Description

The Han lab studies how mitochondrial metabolism regulates lung stem/progenitor cells by focusing on the different functions of each mitochondrial electron transport chain complex. We are particularly interested in how lung epithelial cells repair after injury and what factors lead to aberrant repair resulting fibrosis. Mitochondrial dysfunction is commonly observed in patients with severe pneumonia and/or pulmonary fibrosis. Using elaborately designed genetic knock-out and knock-in mouse systems, we are testing whether mitochondrial electron transport chain complexes are necessary for proper lung epithelial stem/progenitor cell differentiation.  We use viral pneumonia as a model of lung injury and repair in animals. Findings from these studies can be directly applied to the patients hospitalized for pneumonia, influenza, and SARS-CoV-2 infection in our hospital.     

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

Publications

See Dr. Han's publications on PubMed

Contact

Dr. Han

 Congcong He Lab

Studying how autophagy (“self-eating”) carries out intracellular quality control, and regulates metabolism and behaviors in health and disease

Research Description

The research in my lab is centered on intracellular quality control mediated by autophagy (“self-eating”), a lysosomal degradation pathway essential for nutrient recycling, cellular maintenance and physiological function. Autophagy is induced by stress conditions such as fasting and exercise, and allows cells to adapt to changing nutrient and energy demands through protein catabolism. Our interest focuses on the roles and mechanisms of autophagy in the regulation of metabolism and in the pathogenesis of metabolic and neurological disorders, including obesity, type 2 diabetes, neurodegeneration, and drug abuse. Malfunction of autophagy is implicated in a variety of diseases, such as metabolic disorders, neurodegeneration, cancer, infection and aging; conversely, we have shown that upregulation of autophagy mediates exercise-induced metabolic benefits and protects Alzheimer’s mice from neurodegeneration. We are also interested in demonstrating how the autophagy machinery recognizes various cargos for catabolic metabolism, including aggregate-prone proteins, secretory proteins and membrane receptors, in metabolic organs and in different neuronal cell types in the brain, and studying how such degradation leads to metabolic and behavioral alterations.

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

 Thomas Hope Lab

Studying the posttranscriptional regulation of intronless viral messages

Research Description

We study the posttranscriptional regulation of intronless viral messages. Intronless messages must be efficiently processed in the absence of splicing. Therefore, intronless messages must uncouple RNA processing and export from the splicing process making a simpler model system. We are currently focused on the posttranscriptional regulatory element (PRE) of the Hepadnaviruses, including hepatitis B virus (HBV) and woodchuck hepatitis virus (WPRE). Our goal is to understand the novel mechanism of the stimulation of heterologous gene expression by the WPRE. Understanding WPRE function will allow the development of even more efficient gene expression for a variety of applications from gene therapy to large scale protein production.

Although much is known about the molecular biology of HIV, little is known about the details of interactions between the virus and cellular components such as the cytoskeleton. To gain insights into these processes we are combining the disciplines of virology and cell biology to develop the field of cellular virology. We are especially excited by new methods we have developed – such as time-lapse analysis and fluorescent tagging – that allow for HIV to be visualized in living cells.

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

Publications

See Dr. Hope's publications on PubMed.

Contact

Contact Dr. Hope at 312-503-1360.

Lab Staff

Research Faculty

Ann Carias, Gianguido Cianci, Katarina Kotnik Halavaty, Joao Mamede, Danijela Maric

Postdoctoral Fellows

Muhammad Shoaib Arif, Koree Wee Ahn, Yanille Scott, Tahmina Sultana, Roslyn Taylor, Yanique Thomas

Lab Manager

Michael McRaven

Graduate Student

Faisal Nuhu

Technical Staff

Edward Allen, Meegan Anderson, Lisette Corbin, Flora Engelmann, Joseph Griffin, Megan Halkett, Jared Schooley, Divya Thakkar, Sixia Xiao

Program Staff

Debra Walker

Temporary Staff

Bryan Luna, Ewa Tfaily

 Luisa Iruela-Arispe Lab

Molecular regulation of angiogenesis and vascular homeostasis

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

 

 

 Bin Jiang Lab

Vascular disease modeling, tissue engineering and regenerative medicine

Research Interests

The Jiang laboratory is an interdisciplinary research program of vascular surgery and biomedical engineering. The primary focus of our work is on vascular repair and regeneration for a variety of vascular diseases and conditions. We use a combination of innovative technologies, including induced pluripotent stem cells (iPSCs), biomaterials, and non-invasive imaging to develop patient-specific, tissue engineered vascular constructs. Currently, the laboratory is investigating the mechanisms behind vascular calcification and abdominal aortic aneurysm with novel disease models in vitro and in vivo. Additionally, we explore the role of microenvironment in the differentiation of vascular cell phenotypes in health and disease. Ultimately, the scientific discoveries and engineering solutions developed by our research program will benefit patients suffering from vascular diseases.

For more information, visit Dr. Jiang's faculty profile page or the Jiang lab website

Publications

See Dr. Jiang's publications.

Contact

Dr. Jiang

 Julie Kim Lab

The role of progesterone receptor in uterine diseases

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.

 Hiroaki Kiyokawa Lab

Investigating the roles of cell cycle-regulatory proteins in differentiation, senescence and tumorigenesis and the cell cycle control in endocrine and reproductive organs

Research Description

We are interested in the basic mechanisms of cell cycle control, cellular senescence/immortalization and malignant transformation, with a focus on protein regulation by ubiquitination. We previously demonstrated that cell cycle regulators such as p27Kip1, CDK4 and CDC25A play highly tissue-specific roles in development and oncogenesis. Ubiquitination, the covalent modification of substrate proteins with the small 76-residue protein ubiquitin, exerts diverse regulation of the fate of substrates, including the cell cycle regulators, e.g, promoting proteolysis, altering subcellular localization and modulating enzymatic activities. Our current research is aimed at revealing novel functions of ubiquitination enzymes and their substrates in development and cancer, which is expected to identify new therapeutic targets against human diseases. The laboratory uses a combination of protein engineering, proteomics, bioinformatics, cell biological techniques such as time-lapse microscopy and 3-D culture and genetically engineered mouse models. Keywords: cell cycle, ubiquitin, ubiquitination, cancer initiation, cancer progression, knockout mice, transgenic mice, breast cancer, cyclin, diabetes, pituitary, development.

Recent Findings

  • There is a unique regulation of cell cycle progression in neuroendocrine tissues such as pancreatic islets and pituitary glands of CDK4-null mice; we have shown that in this particular type of cell cycle, Cdk4 plays an indispensable and rate-limiting role
  • CDC25A phosphatase, which activates CDK2 and CDK1, is an oncogene that plays a rate-limiting role in initiation and progression of various tumors, including breast cancer

Current Projects

We are currently investigating roles of the cell cycle machinery in differentiation, tumorigenesis and apoptosis, by combinations of mouse models and molecular analyses.

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

Publications

See Dr. Kiyokawa's publications on PubMed.

Contact

Contact Dr. Kiyokawa at 312-503-0699.

Lab Staff

Technical Staff

Cade Brittain, Alison Rogozinski

Temporary Staff

Asia Owais

 Tsutomu Kume Lab

The Kume Lab’s research interests focus on cardiovascular development, cardiovascular stem/progenitor cells and angiogenesis.

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

 Laimonis Laimins Lab

Molecular biology of human papillomaviruses (HPV) and their association with cervical cancer

Research Description

Our efforts are divided into two main categories:

  • An examination of how the viral oncoproteins E6 and E7 contribute to the development of malignancy
  • Studies on the mechanisms controlling the viral life cycle in differentiating epithelia

More than 100 distinct types of human papillomavirus have been identified and approximately one-third specifically target squamous epithelial cells in the genital tract. Of these genital papillomaviruses, a subset including types 16,18 and 31 have been shown to be the etiological agents of most cervical cancers.

One of our goals is to understand why infection by specific HPV types contributes to the development of malignancy. For these studies we have examined the interaction of the oncoproteins E6 and E7 with cellular proteins. In particular, E6 binds the p53 protein and facilitates its degradation by a ubiquitin-mediated pathway. It also activates telomerase as well as associates with PDZ-domain containing proteins. The interactions of the E6 and E7 proteins with these cellular proteins are being examined at both the biochemical and genetic level.

In examining the papillomavirus life cycle, we have used organotypic tissue culture systems to faithfully reproduce the differentiation program of epithelial cells in the laboratory. Using this system, the viral life cycle has been duplicated.  We are studying the mechanisms that regulate viral DNA replication, cell entry, immune evasion and gene expression. These studies should provide insight into viral pathogenesis as well as the mechanisms regulating epithelial differentiation.

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

Publications

See Dr. Laimins' publications on PubMed.

Contact

Contact Dr. Laimins at 312-503-0648 or the lab at 312-503-0650.

Lab Staff

Postdoctoral Fellows

Ekaterina Albert, Elona Gusho, Takeyuki Kono, Sreedhar Pujari

Technical Staff

Archit Ghosh, Paul Hoover, Paul Kaminski, Brian Studnicka

 Monica Laronda Lab

Pediatric Fertility & Hormone Preservation & Restoration

Research Description

Our research addresses fundamental regenerative medicine questions through the lens of reproductive biology. The main objective of our lab is to develop a patient-specific ovarian follicle niche that will support systemic endocrine function and fertility in women and girls who were sterilized by cancer treatments, have disorders of sex development or were exposed to other factors that could result in premature ovarian failure or sex hormone insufficiency. This research is a part of the Ann & Robert H Lurie Children’s Hospital Fertility and Hormone Preservation and Restoration Program that bridges basic science, translational research and clinical practice.

Publications

See Dr. Laronda's publications in PubMed.

Contact

Email Dr. Laronda

 Jennie Lin Lab

The Lin lab studies the functional significance of human-based genomic and transcriptomic discoveries in cardiometabolic and kidney diseases.

Research Description

Elucidating How Genotype Lease to Phenotype in Cardiometabolic and Renal Disease

Unbiased human-based discovery efforts, such as genome-wide and exome-wide association studies, have identified many genetic loci for complex, disease-relevant traits. These genetics studies have provided invaluable data implicating novel loci in disease development and progression, but require functional follow-up to elucidate the mechanistic underpinnings driving the associated findings. A focus of the lab is to interrogate, through experimental wet-bench approaches, the functional significance of novel loci for blood lipids levels and measurements of renal function in the hopes of gaining new insights into pathways relevant to cardiometabolic and renal disease, respectively.

In particular, we are studying the role of A1CF, a gene encoding the RNA-binding protein APOBEC1 complementation factor and recently implicated as a locus for (1) elevated plasma triglycerides (Liu et al., Nature Genetics 2017), (2) estimated glomerular filtration fraction in non-diabetic individuals (Pattaro et al., Nature Communications 2016) and (3) serum urate (Kottgen et al., Nature Genetics 2013). We have already discovered that A1CF's actions extend beyond its canonical role of facilitating the editing of APOB mRNA, and we are currently integrating studies using animal and human cellular models to investigate how A1CF contributes to these associated traits.

Using iPSC and Genome Editing Technologies to Study Human Diseases

Although rodent models have contributed greatly to our understanding of human diseases, the genomic and physiologic differences between rodent and human have presented challenges in translating bench-based findings into clinic. To circumvent this roadblock, our lab is using iPSC-derived organoid models to study the effects of DNA variants within the native human genomic context. Using CRISPR-based technology to introduce or correct mutations in human iPSCs, we are modeling the effects of disease-associated mutations on cellular phenotype.

RNA-centric Approach to Studying Kidney Disease

Building upon A1CF-related work and previous experience with long non-coding RNA, we are studying the role of transcriptome-level regulation in the context of kidney disease. We have discovered that A1CF is a novel regulator of alternative splicing in both the liver and kidney, and we are currently working on how A1CF's regulation of splicing may influence intracellular metabolism. We are also studying how human-specific long non-coding RNAs influence gene expression and cellular phenotypes.

For more information, visit the Faculty Profile of Jennie Lin or visit the Lin Lab Website

Publications

See Dr. Lin's publications in PubMed.

Contact

Email Dr. Lin

Phone 312-503-1892

 Donald Lloyd-Jones Lab

Cardiovascular disease epidemiology, risk estimation and prevention

Research Description

Dr. Lloyd-Jones’ research interests lie in cardiovascular disease epidemiology, risk estimation and prevention. A main focus of his research has been investigation of the lifetime risks for various cardiovascular diseases and factors that modify those risks. Other areas of interest include cardiovascular disease risk estimation using novel biomarkers, imaging of subclinical atherosclerosis and the epidemiology of hypertension. His clinical and teaching interests lie in general cardiology with a focus on prevention.

For more information, visit the faculty profile of Donald Lloyd-Jones, MD, ScM.

Contact

Email Dr. Lloyd-Jones

Phone 312-908-1718

 William Lowe Lab

Genetic determinants of maternal metabolism and fetal growth

Research Description

A major interest of the Lowe laboratory is genetic determinants of maternal metabolism during pregnancy and the interaction between the intrauterine environment and genetics in determining size at birth.  This interest is being addressed using DNA and phenotype information from ~16,000 mothers and their babies who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.  A genome wide association study using DNA from mothers and babies from four different ancestry groups has been performed, with several different loci demonstrating genome-wide significant association with maternal and fetal traits.  Replication studies have confirmed the identified associations.  Studies are now underway now to identify the causal variants and their functional impact.  In related studies performed with investigators at Duke, targeted and untargeted metabolomic studies are underway to determine whether metabolic signatures characteristic of maternal obesity and/or hyperglycemia can be identified in mothers and babies. Integration of metabolomic and genomic data is also planned to more fully characterize maternal metabolism during pregnancy and its interaction with fetal growth.  Finally, a HAPO Follow-Up Study has been initiated in which a subset of the HAPO mothers and babies (now 8-12 years of age) will be recruited to examine the hypothesis that maternal glucose levels during pregnancy are positively correlated with metabolic measures in childhood, including adiposity, lipidemia, glycemia and blood pressure.

For further information visit Dr. Lowe's faculty profile page

Publications

View Dr. Lowe's publications at PubMed

Contact

Email Dr. Lowe

Phone 312-503-2539

 Aline Martin Lab

The Martin Lab investigates the role of the skeleton in the endocrine regulation of mineral metabolism and the cardiovascular complications of mineral and bone diseases.

Our research program focuses on the contribution of the skeleton to the mineral balance in the body.  Bone produces a hormone, Fibroblast Growth Factor (FGF)-23, that participates in this balance.  However in mineral metabolism disorders, such as in chronic kidney disease, the massive production of FGF23 is associated with negative outcomes and mortality.  By understanding the mechanisms that control the production of FGF23, our goal is to develop new therapeutic strategies and improve outcomes in mineral metabolism disorders.  To this goal, we perform basic and translational research using a combination of genetics, molecular biology, proteomics, histology and advanced imaging techniques. 

A major focus of the lab is to investigate the transcriptional and post-translational regulation of FGF23 within the bone cells.  In particular, we study the specific role of a known regulator of FGF23, Dentin Matrix Protein 1 (DMP1), on these regulations and on osteocyte biology in the context of diseases associated with FGF23 excess (chronic kidney disease, hypophosphatemic rickets …).  A second focus is to investigate the mechanisms involved in negative outcomes associated with FGF23 excess, including bone mineralization defects, cardiac hypertrophy and cognitive defects.  Our team works in collaboration with the Center for Translational Metabolism and Health and the Division of Cardiology at Northwestern, and with multiple additional collaborators and partnerships around the world.

The Martin Lab is sponsored by the National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and by the Northwestern Women’s Health Research Institute.

Publications

For more information view Dr. Martin's Faculty Profile or  view publications by PubMed

Contact Us

Contact Dr. Martin at 312-503-4160 or the Martin Lab at 312-503-4805, or by email.

 Daniela Matei Lab

Mechanisms of ovarian cancer metastasis and novel therapeutics for ovarian cancer

Research Description

My laboratory studies mechanisms of ovarian cancer metastasis and novel therapeutics for ovarian cancer. The general theme is translation between bench and clinic; with laboratory research forming the foundation for clinical experiments. 

One direction of investigation relates to the interaction between cancer cells and the peritoneal stroma.  We described the functions of tissue transglutaminase as an interacting partner of b-integrins and regulator of peritoneal metastasis.  Based on new mechanistic insight into the roles of this enzyme in ovarian cancer, we discovered and began characterizing new small molecule inhibitors for the transglutaminase-fibronectin-integrin interaction that are being developed as anti-cancer agents. We are studying these new inhibitors in-vitro and in in-vivo models of ovarian cancer metastasis.

Another area of research focusses on the characteristics and therapeutic vulnerabilities of ovarian cancer stem cells.  We used small molecule inhibitors that target ALDH1A1 to block the tumorigenic capacity of these cancer-initiating cells.  We are studying how ALDH1A1 inhibitors alter stem cell specific signaling and how ALDH1A1 is involved in maintaining the cancer stem cell properties. 

More recently we identified new metabolic alterations involving fatty acids desaturation in cancer stem cells.  We have targeted lipid metabolism using small molecule inhibitors and are studying the mechanisms by which these metabolic changes contribute to the maintenance and tumorigenicity of cancer stem cells.  Future goals are to refine the use of ALDH and fatty acid desaturases inhibitors to target cancer stem cells residual after chemotherapy and to eradicate the disease.

Another important direction of investigation is epigenetic modulation as a method of resensitization to platinum in ovarian cancer.  We successfully brought to the clinic the concept that epigenetic modulation re-sensitizes chemotherapy-resistant ovarian tumors to carboplatin.  I led a randomized multi-institutional clinical trial testing the effects of DNA hypomethylating agents and carboplatin compared to standard chemotherapy.  We are now analyzing the genome and epigenome of platinum resistant ovarian cancer using specimens from this trial.  We have identified several pathways that are associated with platinum resistance and respond to hypomethylating agents.  We have designed a new strategy to target pathway-specific DNA methylation and are testing the effects of this intervention on cell signaling and gene expression profiles in ovarian cancer cells.  

Publications

View Dr. Matei's publications on PubMed

Contact

Email Dr. Matei

Phone 312 503-4853

 Elizabeth McNally Lab

Genetic mechanisms responsible for inherited human diseases

Research Description

My laboratory studies genetic mechanisms responsible for inherited human diseases including heart failure, cardiomyopathy, muscular dystrophy, arrhythmias, aortic aneurysms. Working with individuals and families, we are defining the genetic mutations that cause these disorders. By establishing models for these disorders, we can now begin to develop and test new therapies, including genetic correction and gene editing.


For lab information and more, see Dr. McNally's faculty profile or visit the McNally Laboratory site.

Publications

See Dr. McNally's publications on PubMed.

Contact

Email Dr. McNally

Phone  312-503-5600

 Stephen Miller Lab

Elucidation of mechanisms of pathogenesis and immune regulation of autoimmune disease, allergy and tissue/organ transplantation

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 IferganJoseph Podojil, Dan Xu

Adjunct Faculty

John Galvin

Postdoctoral Fellows

Andrew Cogswell, Gabriel Lorca, Tobias Neef, Haley Titus

Lab Manager

Sara Beddow

Technical Staff

Ming-Yi Chiang, Lindsay Moore

Visiting Scholars

Michael Boyne, Daniel Getts

Temporary Staff

Grant Primer

 Jason Miska Lab

Studying the metabolism of immune cells in brain tumors 

Research Description

The goal of the Miska laboratory's is to determine how the metabolism of immune cells within brain tumors contributes to immune suppression and tumor recurrence. Furthermore, we seek to manipulate these metabolic pathways in a clinically relevant manner to improve patient outcomes for this deadly disease. Currently, we are exploring how the unique metabolism of tumor-associated myeloid cells (TAMCs) promote their survival, immunosuppression, and tumor brain progression. We have discovered that inhibiting the downstream products of arginine metabolism is a useful strategy for promoting anti-tumor immune responses. Our laboratory also performs immunological monitoring for clinical trials in brain tumor patients by monitoring immune phenotypes, T-cell reactivity, and changes in systemic cytokines that occur with therapeutic administration.

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

Publications

See Dr. Miska's publications.

Contact

Contact Dr. Miska 

 

 Clara Peek Lab

Circadian clock control of fuel selection and response to nutrient stress

Research Description

The Peek Lab is focused on understanding the interplay between hypoxic and circadian transcriptional pathways both at the genomic and nutrient signaling levels. Peek aims to uncover novel mechanisms linking circadian clocks to the control of metabolic function and disease, such as type 2 diabetes and cancer. The lab utilizes metabolic flux analyses, in vivo metabolic and behavior monitoring, and next-generation sequencing in their research.

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

Publications

See Dr. Peek's publications on PubMed.

Contact

Contact Dr. Peek at 312-503-6973.

Lab Staff

Graduate Student

Kaitlyn Hung

Technical Staff

Noah Hamlish, Adam Steffeck, Abhishek Thakkar

 Arthur Prindle Lab

Synthetic biology in microbial communities

Research Description

The Prindle lab is interested in understanding how molecular and cellular interactions give rise to collective behaviors in microbial communities. While bacteria are single celled organisms, we now understand that most bacteria on our planet reside in the context of structured multicellular communities known as biofilms. However, most bacterial research is still performed on domesticated lab strains in well-mixed conditions. We simply do not know enough about the biology and behavior of the most pervasive life form on our planet. It is our goal to discover and understand these behaviors so that we may apply our understanding to engineer biomolecular systems as solutions to challenging biomedical problems, such as antibiotic resistance. To do this, we also work on developing technologies that can characterize collective metabolic and electrochemical dynamics that emerge in the context of biofilms.

For more information, see Dr. Prindle's lab website.

Publications

See Dr. Prindle’s publications on PubMed.

Contact

Contact Dr. Prindle

 Susan Quaggin Lab

Uncovering the molecular mechanisms of diabetic vascular complications, thrombotic microangiopathy, glomerular diseases and glaucoma

Our lab focuses on the basic biology of vascular tyrosine kinase signaling in development and diseases of the blood and lymphatic vasculature.  Our projects include uncovering the molecular mechanisms of diabetic vascular complications, thrombotic microangiopathy, glomerular diseases and glaucoma.  Utilizing a combination of mouse genetic, cell biologic and proteomic approaches, we have identified key roles for Angiopoietin-Tie2 and VEGF signaling in these diseases.  Members of the lab are developing novel therapeutic agents that target these pathways.  

For more information, please see the faculty profile of Susan Quaggin, MD

Publications

See Dr. Quaggin's publication in PubMed

Contact

Email Dr. Quaggin

 Karen M. Ridge Lab

The Ridge Lab investigates the role of intermediate filaments in lung pathophysiology

The cytoskeletal protein vimentin plays a key role as a scaffold for the formation and activation of intracellular protein complexes. One such complex is the NLRP3 inflammasome, which assembles in response to danger signals such as influenza A virus or ATP released by damaged cells to produce mature IL-1β and IL-18. These inflammatory cytokines can induce lung injury, which can lead to fibrosis. One of our current goals is to pinpoint vimentin’s role in inflammasome assembly and activation.

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

 Paul Schumacker Lab

Oxygen sensing in embryonic development, tissue responses to hypoxia and tumor angiogenesis.

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

 Vipul Shukla Lab

Deciphering alternative DNA codes in normal and cancer genomes

Research Description

Our lab applies state-of-the-art genetics, genomics, molecular biology and cell biology techniques to decipher the functions of cytosine modifications and structural conformations as alternative DNA codes in the genome. Decades of research have established how specific DNA sequences control genomic states associated with transcription, chromatin modifications and topological compartmentalization. However, besides helical, linear sequences, the DNA in the genome commonly adopts unusual, non-helical structural conformations and we want to understand the significance of these alternative structural conformations in normal cellular physiology and associated pathologies. As first-steps towards understanding the functions of alternative DNA structures, our lab is studying their abundance in normal and cancer genomes, epigenetic mechanisms regulating their localization and dynamics, and cellular pathways controlled by these structures. These studies have broad implications on many established paradigms in genome biology and will address fundamental questions related to origins of several different cancers with the ultimate goal of identifying vulnerabilities that could be therapeutically targeted.

Our lab also holds strong interest in understanding basic molecular mechanisms regulating immune responses. We are particularly interested in understanding how changes in the metabolic outputs, that are associated with distinct stages of B (and T) cell differentiation impacts their epigenetic landscapes. We aim to uncover these mechanisms with the ultimate objective to design approaches by which we could engineer the desired epigenetic states in immune cells to enhance the fidelity of immune responses.

For lab information and more, see Dr. Shukla's faculty profile or visit the Shukla Laboratory site.

Publications

View Dr. Shukla's publications on PubMed.

Contact

Email Dr. Shukla

 

 Benjamin Singer Lab

Exploring respiratory failure

Research Description

The Singer Lab focuses on determinants of resolution and repair of acute lung inflammation and injury. Our ultimate goal is to unravel the factors controlling resolution and repair and exploit those factors as therapies for acute respiratory distress syndrome (ARDS)—a devastating disorder responsible for the deaths of tens of thousands of people each year.

For more information, visit the Benjamin Singer Lab site or his faculty profile page.

View Dr. Singer's publications on PubMed.

Contact Us

Email Dr. Singer or contact at 312-908-8163.

 Jacob I. Sznajder Lab

The Sznajder Lab investigates the mechanisms of acute lung injury as related to aging, high CO2, low oxygen, lung cancer and influenza infection.

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

Patricia Brazee
DGP Graduate Student
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

Weronika Zuczek
Research Technologist I
312-503-1685

 Benjamin Thomson Lab

Links between endothelial function and vision

Research Interests

Endothelial dysfunction is a major cause of vision loss, playing a key role in diseases including age-related macular degeneration, diabetic retinopathy and glaucoma. Using mouse genetics, animal disease models and a combination of single cell RNA-sequencing and histological approaches, our lab is focused on understanding the role of the vasculature in these diseases, including glaucoma and age related macular degeneration. By elucidating molecular connections between endothelial dysfunction and vision loss, we aim to identify novel therapeutic targets and translate these discoveries into patient care.

While endothelial dysfunction is a component of many eye diseases, the importance of ocular vasculature in age related macular degeneration is widely understood and is the basis for the life-altering anti-VEGF therapies that target choroidal neovascularization associated with these conditions. The choroid and choriocapillaris (CC) form a unique vascular bed in the back of the eye that is vital for maintenance of the retinal photoreceptors and retinal pigment epithelium (RPE). In addition to the well-described link with AMD, choroidal dysfunction is tied to the poorly understood spectrum of pachychoroid diseases including polypoidal choroidal vasculopathy (PCV), which can lead to irreversible loss of vision. Despite their clinical impact, little is known about pathogenesis or optimal treatment of PCV and other pachychoroid diseases, or why some patients with defects in the choroidal vasculature develop geographic atrophy or neovascular AMD and others PCV. Ongoing research in our lab seeks to answer this question, using animal models, single cell RNA sequencing and in vivo imaging to gain mechanistic insights into pachychoroid biology, understand mechanisms by which choriocapillaris attenuation lead to choroidal dysfunction, and identify genes and pathways which can be targeted for future therapies. 

Publications

For additional information, visit the faculty profile of Dr. Thomson

View Dr. Thomson's publications at PubMed

Contact

Contact Dr. Thomson

 

 Edward Thorp Lab

The Thorp laboratory studies how immune cells coordinate tissue repair and regeneration under low oxygen, such as after a heart attack.

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

 Praveen Thumbikat Lab

Studying benign prostate diseases, chronic prostatitis/chronic pelvic pain syndrome

Research Description

The focus of research in the laboratory is to understand the pathogenesis of genitourinary diseases with emphasis on benign prostate disease in humans. Inflammation is a significant finding in a variety prostate diseases including prostatitis, BPH and prostate cancer. We study microbial and autoimmune mediated inflammation and innate and adaptive immune mechanisms in prostate disease. A particular area of interest is chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a debilitating medical condition characterized by dysuria and pain.  Projects in the lab use a combination of in vitro studies, animal models and clinical specimen assays to examine questions of interest such as the role of chemokines and T-cells in chronic pelvic pain.

For more information, see the faculty profile of Praveen Thumbikat, PhD.

Publications

View Dr. Thumbikat's publications at PubMed

Contact

Email Dr. Thumbikat

Phone 312-503-1050

 Margrit Urbanek Lab

Susceptibility genes for complex diseases

Research Description

Dr. Urbanek’s research focuses on the identification of susceptibility genes for complex diseases.  Her approach to this research is to use family-based gene-mapping techniques and population-based association studies in conjunction with molecular techniques to identify and verify genes and pathways contributing to the pathogenesis of genetically complex diseases. Specifically, she is carrying out studies to identify susceptibility genes for polycystic ovary syndrome (PCOS) that map to Chr19p3.13.  She has previously shown that this region shows linkage and association with PCOS in a large set of families.   Other projects focus on identifying candidate genes for gestational diabetes and glycemic control during pregnancy and identifying genetic variation contributing to extreme obesity

Research Topics

Identification of sequence variants in PCOS candidate genes
Identification of candidate genes for contributing glycemic control during pregnancy and to gestational diabetes
Genetic variation contributing to extreme obesity
Linkage and family-based association studies
Haplotype analysis
Genome-wide association studies

For more information, visit Dr. Urbanek's faculty profile page.

Publications

View Dr. Urbanek's publications at PubMed.

Contact

Email Dr. Urbanek.

Phone 312-503-3658

Lab Staff

Graduate Students

Lidija Gorsic

 Douglas E. Vaughan Lab

Plasminogen activator system in cardiovascular disease

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

 Jindan Yu Lab

Understanding the genetic and epigenetic pathways to prostate cancer.

The Yu lab focuses on cancer genomics and translational cancer research.  At the current stage, our primary research interest is to understand aberrant transcriptional and epigenetic regulation of prostate cancer and to translate such knowledge into clinical applications.  We utilize high-throughput genomic techniques in combination with bioinformatics/statistical analysis to generate testable hypothesis.   We then test these hypotheses using traditional molecular and/or cellular biological approaches and examine the functional relevance of these innovative regulatory pathways in vitro and in vivo using cell lines and mouse models.  Based on the genetic and epigenetic underpinning of the disease, we pursue translational research to develop new biomarkers and novel therapeutics strategies for advanced prostate cancer.

Select Publications

Kim J, Lee Y, Lu X, Song B, Fong KW, Cao Q, Licht JD, Zhao JC, Yu J.  Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator.  Cell Reports. 2018 Dec 04. PMID: 30517868

Fong KW, Zhao JC, Song B, Zheng B, Yu J.  TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression.  Nat Commun. 2018 Nov 27. PMID: 30479348

Fong KW, Zhao JC, Kim J, Li S, Yang YA, Song B, Rittie L, Hu M, Yang X, Perbal B, Yu JPolycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer.  CancerRes. 2016 Nov 4. PMID: 27815387

View all lab publications via PubMed.

For more information, visit the faculty profile page of Jindan Yu, MD/PhD or visit the Yu Laboratory website.

Contact Us

Contact Dr. Yu at 312-503-2980 or the Yu Lab at 312-503-3041.

Lab Staff

Will Ka-Wing Fong
Research Assistant Professor

Jonathan Zhao, MD, MS
Research Associate Professor

Nathan Damaschke, PhD
Postdoctoral Fellow

Yongik Lee, PhD
Postdoctoral Fellow

Xiaodong Lu, PhD
Postdoctoral Fellow

Gang Zhen, PhD
Postdoctoral Fellow

Xiaoyan Zhu, PhD
Postdoctoral Fellow

Galina Gritsina
Graduate Student

Kevin Park
Graduate Student

Rakshitha Jagadish
Masters Student

 Ming Zhao Lab

The Zhao lab develops diagnostic markers and investigates pathogenic mechanisms of human diseases based on changes in cellular membranes.

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

 Youyang Zhao Lab

The Zhao Lab studies the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury as well as endothelial and smooth muscle cell interaction in the pathogenesis of pulmonary vascular diseases.

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

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