Research into the biological functions of sugars and lipids.
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, and 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.
The Bochner lab studies cells and siglec receptors (especially Siglec-8 and Siglec-F) involved in allergic inflammation, focusing mainly on eosinophils, mast cells and basophils in humans and mice.
Our primary research interests are in eosinophil- and mast cell-associated diseases, including asthma, hypereosinophilic syndromes and systemic mastocytosis. We have a particular interest and focus on understanding the function of Siglec-8, an inhibitory and sometimes pro-apoptotic receptor expressed on human eosinophils, basophils and mast cells, and how it can be targeted for clinical benefit. Animal models are used to study its closest counterparts, such as Siglec-F. In studies involving carbohydrate biochemistry and glycoproteomics, the lab is isolating and characterizing potential glycan ligands for Siglec-F and Siglec-8. Finally, we are interested in food allergy and anaphylaxis, and are exploring new ways to prevent allergic reactions in vitro and in vivo.
The majority of our work is funded by two NIH grants:
- “Targeting Siglec-8/-F to Treat Eosinophil and Mast Cell Related Disorders” from NIAID R01 AI072265 (02/01/13-01/31/18, Bochner, PI). Studies in this grant will explore whether Siglec-8, a molecule selectively expressed by eosinophils and mast cells, can be targeted for both diagnostic and therapeutic purposes in allergic, gastrointestinal and malignant diseases.
“Glycobiology of Inflammatory Lung Diseases” from NHLBI P01 HL107151 (04/01/11-05/31/18, Ronald Schnaar, PI; Bochner is PI of Project #1). This project defines anti-inflammatory sugar molecules and uses them to develop new treatments for lung diseases, employing among other approaches newly developed humanized eosinophil-specific Siglec-8 knock-in mice. This is a collaborative study involving labs at Johns Hopkins (Ron Schnaar et al), The Scripps Institute (James Paulson, Corwin Nycholat et al), University of Georgia (Mike Tiemeyer et al) and Yale (Zhou Zhu et al).
View lab publications via PubMed.
Contact Dr. Bochner at 312-503-0068 or the Bochner Lab at 312-503-1396.
Senior Research Technologist
Daniela Janevska, BS
Graduate Student and PhD candidate
Liliana Moreno, PhD
Research Associate Professor
Jeremy O’Sullivan, PhD
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.
See Dr. Green's publications in PubMed.
For more information, please see Dr. Green's faculty profile.
Contact Dr. Green at 312-503-1812 or the Green Lab at 312-503-0089
David Hillburn, MD
Xiaoying Liu, PhD
Studying the posttranscriptional regulation of intronless viral messages
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.
See Dr. Hope's publications on PubMed.
Contact Dr. Hope at 312-503-1360.
Transcriptional control of Fut7 in hematopoietic cells
My laboratory is interested in transcriptional control of leukocyte traffic during inflammation and immunity. Our focus is on glycosyltransferase genes which encode enzymes which contribute to the biosynthesis of glycan ligands for selectins. Selectins are carbohydrate-binding adhesion molecules which control leukocyte recruitment during inflammation as well as homeostatic functions such as lymphocyte recirculation through secondary lymphoid organs and leukocyte traffic to bone marrow. At least four glycosyltransferases which participate in selectin ligand formation have been identified, among which the most important is an a1,3 fucosyltransferase called FucT-VII, encoded byFut7. All evidence suggests thatFut7 is dedicated to selectin ligand formation, yet the molecular genetic basis for its complex pattern of expression is poorly understood. We use molecular biologic, genetic, cell biologic, biochemical and immunological approaches to understand how T cell activation and specific cytokines control expression ofFut7 and selectin ligands in activated T cells, howFut7 gene expression is controlled in hematopoietic stems cells and developing myeloid cells, and howFut7 gene expression is controlled by both transcription factors and cis-acting genetic elements.
For lab information and more, see Dr. Kansas's faculty profile.
See Dr. Kansas's publications on PubMed.
Contact Dr. Kansas at 312-908-3237 or the lab at 312-908-3752.
Roles of chondroitin sulfates and genes/proteins in the chondroitin sulfate biosynthesis pathway in development and disease
My laboratory is interested in the functional roles of chondroitin sulfates and chondroitin sulfotransferase genes in mammalian development, disease, and cellular signaling pathways. Specifically, we have been investigating the roles of the sulfotransferase C4ST-1/CHST11 and its chondroitin sulfate product CS-E in the contexts of breast cancer progression, the pediatric disease Costello syndrome, cardiovascular disease, developmental processes including embryonic stem cell differentiation and cell lineage determination, and in the control of Wnt/beta-catenin and HRAS signaling. Our long-term goal is the development of carbohydrate-based pharmacological interventions for the treatment of human diseases, including cancer and cardiovascular disease.
For more information, view the faculty profile of Michael Klüppel, PhD.
See Dr. Klüppel's publications in PubMed.
Michael Klüppel, Ph.D.
Catherine M. Willis, Ph.D.
Robert Prinz, M.D.
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
Morphogenetic processes in vertebrate embryo
Animal development requires proper specification of different cell types and, at the same time, their organization in to multicellular arrangements such as tissues and organs. My laboratory investigates the mechanisms that control morphogenetic processes in vertebrate embryo. We are studying these processes in the zebrafish (Danio rerio) using a combination of genetic analysis with embryological and molecular methods. The transparency of zebrafish embryos together with the generation of fluorescent transgenic animals allows us to use high-resolution confocal microscopy for in vivo analysis of cell behaviors. Moreover, similarities in developmental programs among all vertebrates make zebrafish an excellent model for investigating human diseases and development.
We are focusing current efforts on the mechanisms that shape the zebrafish head skeleton. We are particularly interested in the role of non-canonical Wnt signaling in cartilage morphogenesis. Mutants with altered non-canonical Wnt signaling pathways exhibit similar cell behavior defects during gastrulation and cartilage morphogenesis. This observation led to the hypothesis that non-canonical Wnt signaling controls cartilage element morphology by modification of chondrocyte behavior. My work on the characterization of the zebrafish knypek gene has revealed a new role for glypicans (heparan sulfate proteoglycan) in controlling morphogenetic movements during gastrulation by promoting non-canonical Wnt11 signaling. We are investigating the function of non-canonical Wnts and their potential co-receptors, glypicans, in chondrocyte differentiation and polarization. Because the initial steps in craniofacial development are similar in all vertebrates, these studies will help understand genetic basis for relatively frequent congenital anomalies causing abnormal development of the hard and soft tissue of the head and neck.
We are also interested in the developmental roles of other glypicans, as these extracellular proteins can play an essential role by interaction with growth factors, chemokines, extracellular matrix proteins, enzymes and enzyme inhibitors. Glypicans can be involved in regulation of ligand-receptor interactions and control of ligand distribution, both within a tissue and on the cell surface. For example, the clinical features of Simpson-Golabi-Behmel overgrowth syndrome, caused by mutation in the gene encoding Glypican 3, suggest that this protein is involved in regulation of cell survival and/or proliferation. One goal of my laboratory is to identify zebrafish glypicans and characterize developmental processes that they are regulating.
For more information view Dr. Topczewski's faculty profile page
View Dr. Topczewski's publications at PubMed
The Zhao lab develops diagnostic markers and investigates pathogenic mechanisms of human diseases based on changes in cellular membranes.
Major research areas in the Zhao lab include:
- 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.
- 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.
- 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.
- 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.
View publications by Ming Zhao in PubMed.
For more information, visit Dr. Zhao's Faculty Profile page
Contact Dr. Zhao at 312-503-3226.
Songwang Hou, PhD
Steven E. Johnson
Ke Ke, PhD
Kaixi Ren, MD