Research into the molecular and cellular control of metabolism and obesity.
Labs in This Area
Role of mitochondria and metabolic processes in cancer growth, cardiac disease and metabolic disorders
Our lab focuses on three major areas of research:
Role of proteins involved in cellular and systemic metabolism
TTP is a protein that binds to AU-rich regions in the 3’ UTR of mRNA molecules and causes their degradation. It has been studied extensively in the field of inflammation. We recently showed that it also plays a role in cellular iron conservation. We have also shown that TTP is a key mediator of cellular metabolic processes. Our studies have demonstrated that TTP regulates glucose, fatty acid and branched-chain amino acid metabolism in the liver and muscle tissue. We also have evidence that TTP directly regulates mitochondrial electron transport chain (ETC) by targeting specific proteins in the ETC complexes. Finally, recent studies demonstrated that TTP also regulates systemic metabolism by targeting FGF-21 expression. We have both TTP Floxed mice (for the generation of tissue specific TTP knockout mice) and TTP knockout mice in the background of TNF-alpha receptor 1/2 knockout mice (to reduce the inflammatory burden). Current studies include: 1) role of TTP in liver metabolism of fatty acids and glucose, 2) effects of TTP on mitochondrial proteins, 3) mechanism of TTP regulation of branched-chain amino acid levels and 4) role of TTP in cardiac metabolism.
Adult cardiomyocytes regenerate at a very low rate, but neonatal cardiomyocytes grow and replicate at a high rate. We have identified specific tandem zinc-finger (TZF) proteins that bind to mRNAs to regulate cardiac regeneration and cardiac development. Our studies suggest that these proteins may alter DNA repair in response to damage by regulating p53 and helicases. Current projects include: 1) identifying the mechanism by which TZF proteins regulate p53 and DNA damage, 2) characterization of the role of helicases in cellular proliferation and regeneration and 3) role of TZF proteins in cardiac development.
Characterization of cellular and mitochondrial iron regulation
Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), which plays a role in mitochondrial iron homeostasis and mitochondrial iron export. Mice with ABCB8 knocked out in the heart develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have shown that a pathway involving mTOR and tristetraprolin, treatment with doxorubicin (an anticancer drug that also causes cardiomyopathy) and SIRT2 protein also impact cellular and/or mitochondrial iron regulation. Current studies in this area include: 1) further characterization of ABCB8 in iron homeostasis in other organs and disorders, 2) characterization of the mechanism for iron regulation by SIRT2, 3) identification of the mechanism by which mTOR is regulated by iron, 4) role of iron in viral infection, particularly HIV, 5) characterization of the effects of iron on mitochondrial dynamics and 6) identification of novel mitochondrial-specific iron chelators.
For more information, see Dr. Ardehali's faculty profile.
See Dr. Ardehali's publications in PubMed.
Transcriptional regulators of inflammation and metabolism
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.
See Dr. Barish's publications in PubMed.
Circadian and metabolic gene networks in the development of diabetes and obesity
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.
See Dr. Bass' publications in PubMed.
Decoding connections between signaling and metabolic networks
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.
See Dr. Ben-Sahra's publications on PubMed.
Contact Dr. Ben-Sahra.
Investigating the application of human induced pluripotent stem cells to study the pharmacogenomics of chemotherapy off-target toxicity and efficacy
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.
- Human induced pluripotent stem cells predict breast cancer patients’ predilection to doxorubicin-induced cardiotoxicity
- Chemically defined generation of human cardiomyocytes
- 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
See Dr. Burridge's publications on PubMed.
Contact Dr. Burridge at 312-503-4895.
Clinical Research Coordinator
Cancer stem cell biology, cellular signaling and therapy responses in human brain tumors, in particular, glioblastoma (GBM)
Integrated genomic analysis by TCGA revealed tat GBMs can be classified into four clinically relevant subtypes, proneural (PN), neural, mesenchymal (Mes) and classical GBMs with each characterized by distinct gene expression signatures and genetic alterations. We reported that PN and Mes glioma stem cells (GSCs) subtypes also have distinct dysregulated signaling pathways. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, invasion/metastasis, angiogenesis and therapy responses of GSCs and GBMs.
1. MicroRNAs (miRs) and non-coding RNAs in GSCs and GBMs – miRs and other small non-coding RNAs act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms. Dysregulated miRs/noncoding RNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of miRs influence GBM malignant phenotypes through interaction with signaling pathways, that in turn, influence proneural (PN)- and mesenchymal (Mes)-associated gene expression in GSCs and GBM phenotypes. We study the molecular consequences and explore clinical applications of modulating miRs and signaling pathways in GBMs. We are establishing profiles of non-coding RNAs in these GSCs and study mechanisms and biological influences of these non-coding RNAs in regulating GSC biology and GBM phenotypes. In addition, we explore novel therapeutic approaches of delivery of tumor suppressive miRs into GSC brain xenografts in animals.
2. Autophagy in GBMs. (Macro)autophagy is an evolutionally conserved dynamic process whereby cells catabolize damaged proteins and organelles in a lysosome-dependent manner. Autophagy principally serves as an adaptive role to protect cells and tissues, including those associated with cancer. Autophagy in response to multiple stresses including therapeutic treatments such as radiation and chemotherapies provides a mechanism for tumor cell to survive and acquire resistance to therapies. Tumors can use autophagy to support and sustain their proliferation, survival, metabolism, invasiveness, metastasis and resistance to therapy. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes on autophagy proteins inhibits autophagy and enhances the efficacy of combination therapies for GBMs. We examine whether cross-talks between miRs, autophagy and oncogenic signaling pathways regulate GSC stemness and phenotypes.
3. Heterogeneity, epigenetic regulation, DNA damage and metabolic pathways in GSCs and GBMs. Intratumoral heterogeneity is a characteristic of GBMs and most of cancers. Phenotypic and functional heterogeneity arise among GBM cells within the same tumor as a consequence of genetic change, environmental differences and reversible changes in cell properties. Subtype mosaicism within the same tumor and spontaneous conversion of human PN to Mes tumors have been observed in clinical GBMs. We explore an emerging epigenetic marker with distinct functions such as DNA methylation together with genetic mapping of these markers to assess their contributions to GBM heterogeneity. In addition, compared with PN GSCs, DNA damage and glycolytic pathways are aberrant active in Mes GSCs. We investigate the mechanisms by which these pathways regulate GSC and GBM phenotypes and responses to therapies.
4. Oncogenic receptor tyrosine kinase (RTKs) signaling, small Rho GTPase regulators in GBM and GSCs: Small Rho GTPases such as Rac1 and Cdc42 modulate cancer cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII and PDGFR alpha promote glioma growth and invasion by distinct mechanisms involving phosphorylation of Dock180, a Rac-specific guanidine nucleotide exchange factor (GEF) and DCBLD2, an orphan membrane receptor. We are currently investigating involvement of other modulators/GEFs and other Rho GTPases in modulating GSC and GBM phenotypes and responses to therapy.
View Dr. Cheng's complete list of publications in PubMed.
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.
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).
Autophagy in metabolic regulation and pathogenesis of metabolic diseases
The research in my lab is centered on autophagy, a lysosomal degradation pathway essential for nutrient recycling, cellular maintenance and physiological function. Autophagy is induced by various stress conditions and allows cells to adapt to changing nutrient and energy demands through protein catabolism. Malfunction of autophagy is implicated in a variety of diseases such as cancer, neurodegeneration, infection and aging. Our interest focuses on the roles and mechanisms of autophagy in the metabolic regulation of mammals and in the pathogenesis of metabolic disorders in human, including obesity and type 2 diabetes. There are many open questions in this largely unexplored area; our research directions include studies of the functions of autophagy in exercise-induced metabolic benefits and investigation of the molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways in the prevention of metabolic dysregulation.
See Dr. He's publications on PubMed.
Contact Dr. He at 312-503-3094.
Genetic determinants of maternal metabolism and fetal growth
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
View Dr. Lowe's publications at PubMed
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.
Contact Dr. Martin at 312-503-4160 or the Martin Lab at 312-503-4805, or by email.
Studying Molecular Mechanisms of Oncogenesis In Acute Leukemia
This is an exciting time for cancer biology especially with the advent of epigenetics and chromatin biology. New molecules with tumor suppressive or oncogenic roles are currently identified and characterized paving the way for new therapeutic ways but at the same time, posing new challenges for researchers. This area of cancer epigenetics is my personal and laboratory's focus. To study this perplexing biology we use patient samples and disease-relevant mouse models.
The Ntziachristos laboratory studies the mechanistic aspects of oncogenesis with an emphasis on transcriptional and epigenetic regulation of acute leukemia. Important questions are related to how oncogenes interact with each other and with epigenetic modulators to influence gene expression programs as well as how their function is related to tri- dimensional (3D) structure of the nucleus and other biological aspects of cancer cells, like metabolism. To address these questions we use high-throughput molecular and cell biology techniques like ChIP-Seq, RNA-Seq, 4C-Seq and HiC, fluorescent in situ hybridization and biochemical analysis in cell lines and primary cells of human origin and tissues of mouse models of disease. In addition to understanding cancer biology these finding help us design and test targeted therapies in preclinical models of leukemia.
For lab information and more, see lab website.
See Dr. Ntziachristos's publications at PubMed.
Dr. Ntziachristos 312-503-5225 or Searle 6-523
Circadian clock control of fuel selection and response to nutrient stress
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.
See Dr. Peek's publications on PubMed.
Contact Dr. Peek at 312-503-6973.
Synthetic biology in microbial communities
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.
See Dr. Prindle’s publications on PubMed.
Contact Dr. Prindle
The Thorp laboratory studies how immune cells coordinate tissue repair and regeneration under low oxygen, such as after a heart attack.
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.
View Dr. Thorp's publications at PubMed
Contact the Thorp lab at 312-503-3140.
Xin-Yi Yeap, MS
Lab Manager and Microsurgery
Susceptibility genes for complex diseases
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
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
Genome-wide association studies
For more information, visit Dr. Urbanek's faculty profile page.
View Dr. Urbanek's publications at PubMed.
Organ and tissue engineering, 3D scaffold systems, induced pluripotent stem cells, stem and progenitor cell differentiation in 3D matrices, regenerative medicine applications
The major area of interest in my laboratory is advancing the state of art in organ regeneration and tissue engineering to develop methods to grow livers and kidneys as a cutting-edge solution to the organ shortage dilemma. Nationally, over 120,000 patients are waiting for solid organ transplantation, yet the number of transplants performed annually falls short of this need by 75%. In the absence of suitable donors for transplantation, organ failure leads to associated health problems, increased healthcare expenditures and death. Organ shortage is a national issue with local impact. In 2010 there were just over 1,050 solitary kidney, liver or heart transplants performed in Illinois, yet 311 patients in the state and more than 6650 nationwide died waiting for an organ.
Our research proposes a multidisciplinary solution to organ shortage by utilizing a tissue engineering approach to rehabilitate the extracellular matrix of organs that are not initially suitable for transplantation. Just-in-time organs, reconstituted with recipient derived progenitor cells, would abrogate the need for long waitlist times and associated waitlist mortality, reduce the reliance on organs from living donors and obviate the need for immunosuppression. Conceptually, these organs would be prepared from a donor matrix using a recipients own cells at the first signs of organ dysfunction. The re-engineered organ would then be ready for implantation when progressive organ failure indicates the need for transplantation.
The traditional paradigm in tissue engineering has been to grow cells on synthetic, polymer scaffolds to recreate the organ or tissue of interest. The limitation of this approach is the scale-up. Beyond a critical distance, diffusion of nutrients and oxygen is not sufficient to support cellular life and a vascular system must be incorporated into the tissue to supply nutrients. It has been technically difficult to design a synthetic micro-vasculature resembling small, terminal capillaries and to combine these structures with functional cells. Our approach challenges this paradigm by using the natural extracellular matrix as a scaffold to support the growth of new cells capable of repopulating the three-dimensional matrix. We have established protocols to remove parenchyma cells from livers and kidneys with a high efficiency of cellular removal and adequate retention of extracellular matrix molecules. We have further repopulated the vasculature of these matrix structures with endothelial cells derived from induced pluripotent stem cell technology. Together, we have partnered with the McCormick School of Engineering at Northwestern University and other leading academic and industrial centers to advance this fast moving field and address the problem of organ shortage.
View publications by Jason Wertheim at PubMed
Lab Phone 312-695-0257
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.
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.
View publications by Youyang Zhao in PubMed.
For more information, visit Dr. Zhao's Faculty Profile page
Email Dr. Zhao
Contact Dr. Zhao’s Lab at 773-755-6355
Zhiyu Dai, PhD.
Research Assistant Professor
Xianming Zhang, PhD.
Research Assistant Professor
Narsa Machireddy, PhD.
Research Assistant Professor
Junjie Xing, PhD.
Colin Evans, PhD.
Varsha Suresh Kumar, PhD.
Xiaojia Huang, PhD
Hua Jin, PhD
Yi Peng, PhD
Mengqi Zhu, M.S.,