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
Characterization of cellular and mitochondrial iron regulation
Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), that 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 mechanisms of iron-mediated cell death that is independent of reactive oxygen species, 4) role of iron in viral infection, particularly HIV, 5) identification of the role of Augmenter of Liver Regeneration (ALR) in cellular iron homeostasis, and 6) identification of novel mitochondrial-specific iron chelators.
Functional characterization of sucrose nonfermenting-1 (NSF1) related kinase (SNRK)
SNRK is a novel protein with sequence homology to AMP kinases, but its function is not yet delineated. We have shown that SNRK inhibits cellular proliferation by blocking the beta-catenin pathway. Transgenic mice that overexpress SNRK in the heart show improved cardiac efficiency by decreasing mitochondrial proton leakage and show protection against ischemia-induced damage through a Trib3-UCP3 pathway. Current studies in this area include: 1) characterization of the effects of SNRK knockout in cancer growth, 2) elucidation of the role of SNRK in cardiac metabolism in SNRK knockouts, and 3) role of SNRK in metabolic diseases such as diabetes.
Characterization of the role of tristetraprolin (TTP) 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, and we recently showed that it also plays a role in cellular iron conservation. We also have evidence that TTP is a key mediator in cellular metabolic processes. We have 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) role of TTP in iron-mediated systemic iron, 3) effects of TTP on mitochondrial proteins, and 4) role of TTP in systemic iron deprivations.
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.
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.
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.
Research Associate Professor
Namratha Sastry (rotating)
Genetic and molecular basis of Polycystic ovary syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is the most common cause of both hormonal-related infertility and oligomenorrhea. This syndrome is characterized by increased androgen biosynthesis and disordered gonadotropin secretion. PCOS is also associated with profound insulin resistance and increased risk for type 2 diabetes. PCOS, and the insulin resistance associated with it, appear to be genetic defects. Moreover, insulin resistance plays a causal role in the abnormalities of ovarian steroidogenesis as well as the anovulation characteristic of PCOS. There are three major research projects currently ongoing, ranging from large-scale family studies through intensive patient-oriented research to animal models and cellular and molecular biology.
The Genetic Basis of PCOS
This research program focuses on identifying the susceptibility genes for PCOS, performing genotype-phenotype analyses and identifying environmental and genetic factors contributing to PCOS familial phenotypes. Studies include family studies with linkage analysis and detailed analyses of reproductive function and insulin action in women with PCOS and their relatives. The approaches include statistical genetics and in vivo studies of insulin action and secretion, as well as pulsatile gonadotropin secretion. One susceptibility gene region has been identified on chromosome 19p13.2 close to the insulin receptor gene. This research is supported by the NIH-NICHD National Cooperative Program for Infertility Research.
Insulin Action and Secretion in PCOS
These studies are focused on identifying the cellular and molecular mechanisms of defects in insulin action and secretion in PCOS. Approaches include detailed in vivo studies of these parameters utilizing techniques such as the euglycemic glucose clamp, frequently sampled intravenous glucose intolerance test with minimal model analysis and graded glucose infusions. Insulin receptor signal transduction is examined in human skeletal muscle biopsies, as well as in human skeletal muscle and adipocyte cultures. Intrinsic defects in insulin receptor signaling have been identified and the mechanisms of these abnormalities are currently under investigation. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Fetal Origins of PCOS
These studies examine the impact of prenatal androgen exposure on insulin action in rodent, primate and sheep models. Studies include examination of lipolysis and insulin signaling in skeletal muscle and adipose tissue and the molecular mechanism of fetal programming. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Scholars will have the opportunity to become involved in phenotype-genotype studies of PCOS families with a strong exposure to the genetics of complex diseases.
For more information, please see Dr. Dunaif's faculty profile.
See Dr. Dunaif's publications in PubMed.
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
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, biochemical analysis e.t.c. 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
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.