Approved Trainers: MTTP
Anthony J. Berdis, Ph.D., Assistant Professor of Pharmacology, co-Leader of the Translational Therapeutics Track, member of the Molecular Pharmacology & Cell Regulation Track.
Inhibition of nucleic acid metabolism is a powerful chemotherapeutic strategy that has one significant pitfall non-selective killing of both diseased and healthy cells. The Berdis laboratory has developed a unique strategy to potentiate the effects of existing chemotherapeutic agents by using their recently developed series of non-natural nucleosides which are preferentially inserted opposite damaged DNA. These non-natural nucleosides inhibit replication opposite damaged DNA and induce apoptosis only in the presence of other chemotherapeutic agents.
Jeffrey L. Blumer, M.D. ,Ph.D., Professor of Pediatrics and Pharmacology, co-Leader of the Translational Therapeutics Track.
Clinical research focuses on the evaluation of the efficacy, safety, and pharmacokinetics of new antimicrobial agents in infants and children. Other studies include detailed evaluation of the pharmacokinetics and pharmacodynamics of intravenous catecholamines in patients undergoing open heart surgery, the rational dosing of sedative agents in mechanically ventilated children, and evaluation of the pharmacokinetic and pharmacodynamic interactions of loop diuretics in children with volume overload. The Blumer lab also investigates the genetic aspects of drug metabolism as they relate to the development of birth defects and pediatric neoplasms.
Robert Bonomo, M.D. Associate Professor of Medicine and Pharmacology, member of the Molecular Pharmacology & Cell Regulation and Translational Therapeutics Tracks.
Research in the Bonomo laboratory investigates the molecular and clinical aspects of bacterial resistance to betalactams antibiotics. One area involves understanding the structure function relationships of the class A beta-lactamase, SHV-1. This chromosomal and plasmid encoded beta-lactamase confers high level resistance to third generation cephalosporins which can render ineffective the most frequently used drugs to treat serious nosocomial infections. The goals are to understand what amino acid substitutions permit evolution of novel substrate profiles and what factors control expression of these periplasmic enzymes.
Matthias Buck, Ph. D., Assistant Professor of Physiology & Biophysics, member of the Membrane, Structural Biology & Pharmacology Track.
Dr. Buck's research program characterizes the structures and the dynamics of proteins involved in protein-protein interactions. Our system of primary interest are the plexin and the Eph family of transmembrane receptors. Both systems play critical roles in development of the cardiovascular as well as the nervous system, but also have direct relevance to the progression of cancers, making them a target for drug design. Protein-protein interactions
determine the basic mechanisms by which signals are transmitted in cells and how signaling is disrupted by mutation in diseased states. Knowing at near-atomic resolution which residues interact in protein-protein interactions will allow us to rationalize their interaction affinity and
specificity. Furthermore, it will provide an opportunity for us to alter the proteins for diagnostic or therapeutic purposes.
Kevin Bunting, Ph.D., Associate Professor of Medicine-Hematology/Oncology and Pathology, member of the Cancer Therapeutics Track.
Dr. Bunting's main area of research is in the field of hematopoietic stem cell biology. Since stem cells are potential targets for treating a wide variety of blood diseases, understanding the basic mechanisms regulating their proliferation, differentiation, self-renewal, mobilization, and
migration is extremely important. Our lab has uncovered major roles for the latent transcription factor STAT5 in growth, long-term competitive repopulating activity, and self-renewal of hematopoietic stem cells. We also found that a Balb/c derived modifier locus that included the Gab2 adapter protein modulated the steady-state engraftment ability. This has led us to now explore mechanisms by which STAT5 and Gab2 cooperate during normal and leukemic hematopoiesis.
Cathleen Carlin, Ph.D., Professor and Acting Chair of Physiology & Biophysics, member of the Membrane, Structural Biology & Pharmacology Track.
The central goal of research in the Carlin laboratory is to understand how signal transduction networks bring about the highly coordinated behavior of cells and tissues during growth and differentiation primarily using the ErbB signaling network comprised of four related receptor tyrosine kinases and more than 30 ligands in humans. The laboratory is interested in the regulation of ErbB trafficking in normal cell physiology and in human 1 pathological states such as adenovirus infection, cancer, and polycystic kidney disease. Multi-faceted experimental approaches are used including analysis of protein complex regulation and function in vitro and in whole cells, genetic approaches to regulating protein expression, assays of dynamic protein sorting, live cell imaging of cellular and sub-cellular protein dynamics, and analysis of abnormalities in cellular and sub-cellular organization in human disease states and animal models.
Martha Cathcart, Ph.D., Professor of Molecular Medicine and Director of the Hughes Training Program in Molecular Medicine, The Cleveland Clinic Foundation and CWRU, member of the Translational Therapeutics Track.
Research in the Cathcart Lab is focused on many aspects of the inflammatory response, including human monocyte activation, regulation of NADPH oxidase generation of superoxide anion, mechanisms of lipid oxidation, expression of 15-lipoxygenase, signal transduction, and regulation of monocyte chemotaxis to MCP1. Current research objectives include Identifying and characterizing the signal transduction pathways regulating superoxide anion production by activated monocytes, exploring the mechanisms involved in IL-13 stimulation of 15-lipoxygenase expression in primary human monocytes, and investigating the regulation of monocyte chemotaxis to MCPI.
Mark Chance, Ph.D., Professor and Director of the Proteomics Center, member of the Membrane, Structural Biology & Pharmacology Track.
The research in Dr. Chance's laboratory is focused high throughput methods to identify the structure and function of large macromolecular complexes in areas relevant to iron transport, DNA mismatch repair, and actin filament assembly and the interaction of cytoskeletal proteins and cell structure. The long term goals of the laboratory are focused on understanding the structure and dynamics of these macromolecular assemblies and how the domain structure of proteins allows and directs protein-protein interactions. Biochemical approaches, mass spectrometry, crystallography, cryo-EM, cross-linking, footprinting, and molecular modeling are used to understand the physiologically relevant functional states. Dr. Chance's laboratory also has a program in examining quantitative protein expression changes in cell and tissues, currently funded projects include examination of protein expression changes in type 1 models of diabetic complications, including drug-receptor targeting.
David Danielpour, Ph.D., Associate Professor of General Medical Sciences/Oncology and Pharmacology, member of the Cancer Therapeutics and Molecular Pharmacology & Cell Regulation Tracks.
The goals of the Danielpour Laboratory are to define the mechanism by which TGF-b functions as a tumor suppressor of the prostate and how such tumor suppression is lost during carcinogenesis of the prostate and progression of prostate cancer from androgen dependence to androgen independence. Our underlying hypothesis is that changes in androgen receptor and PTEN/PI3K/Akt /mTOR signaling pathways that occur during prostate cancer prostate progression promote loss of tumor suppression by TGF-b largely through intercepting Smad3. A variety of approaches are being used to define mechanisms of cross-talk between the above signaling pathways and how they impact on TGF-b-induced growth arrest, apoptosis, tumor suppression and differentiation. Long-term goals of this laboratory are to develop new therapeutic strategies and diagnostic tools for prostate cancer.
Pamela Davis, M.D., Ph.D., Dean, School of Medicine, Professor of Pediatrics, member of the Membrane, Structural Biology & Pharmacology and Translational Therapeutics Tracks.
The laboratory's goal is to understand the pathophysiology of cystic fibrosis (CF) and ultimately to ameliorate or cure it. CF is caused by defects in a gene that encodes a chloride channel, CFTR, but patients succumb to pulmonary infection and inflammation. CF airway epithelial cells and CF mice model the excessive cytokine responses to bacterial stimulation. We found that high dose ibuprofen ameliorates the excessive inflammation clinically, possibly by binding to PPAR-a, a nuclear receptor which can interact with the proinflammatory transcription factor NF-kB to inhibit it. A second line of work is to devise means to deliver normal CFTR gene to the airways of patients. We have constructed DNA nanoparticles consisting of plasmid DNA compacted with polylysine, stabilized with polyethylene glycol, that can transfect airway epithelium in vivo in CF mice and correct the CF chloride transport defect. Promising phase I clinical trials have been completed and Phase II trials are beginning. We are extending the molecular targets for this approach to delivery of siRNA directed against respiratory viruses. Finally, we are interested in the role of FXYD proteins which are induced in CFTR-deficient cells as these proteins appear to have tissue specific consequences for regulation of Na+,K+-ATPase and consequently electrolyte homeostasis.
Clark Distelhorst, M.D., Professor of Medicine and Pharmacology, member of the Cancer Therapeutics and Translational Therapeutics Tracks.
Glucocorticosteroid hormones such as prednisone and dexamethasone are used in the treatment of virtually all types of lymphoid malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, cutaneous T cell lymphoma, and non-Hodgkin lymphoma. The Distelhorst laboratory investigates how glucocorticoids induce apoptosis in order to provide novel insight into a fundamentally important mechanism of apoptosis induction. Understanding the mechanism(s) accounting for apoptosis will allow for the development of novel therapies to overcome resistance to glucocorticoid-induced apoptosis.
Chris Dealwis, Ph.D., Associate Professor of Pharmacology, member of the Membrane, Structural Biology & Pharmacology Track.
Nearly every major process in a cell is carried out by a complex assembly of several proteins. The main focus of the lab involves understanding the structural organization requirements by multiple protein assemblies to facilitate biological function. Our approach is to use a multidisciplinary cycle to study the structure-function relationship of proteins. We also use structure-based drug and protein design to develop novel therapeutics against cancer, Alzheimer’s disease and microbial infections. Biophysical tools such as x-ray & neutron crystallography, molecular modeling, CD, MS, fluorescence spectroscopy and ultracentrifugation are the techniques used in our lab. Specifically, my research focuses on three areas of interest. They are: (1) the structure-function and regulation of ribonucleotide reductase (RNR) by small molecule effectors and its protein inhibitor, the Suppressor of Mec 1 Lethality 1 (Sml1), (2) the structure-function of pathogenic amyloid forming proteins, and (3) the investigation of enzyme catalytic mechanisms, dynamics and solvent structure of macromoleculesusing neutron and ultra-high resolution x-ray diffraction.
George Dubyak, Ph.D., Professor of Physiology & Biophysics, and Pharmacology, co-Leader of the Molecular Pharmacology & Cell Regulation Track, member of the Membrane, Structural Biology & Pharmacology Track.
The laboratory is investigating multiple aspects of nucleotide-based signaling during inflammation with a particular emphasis on the P2X7 receptor, an ATP-gated ion channel that is predominantly expressed in the lymphocytes and macrophages that mediate local proinflammatory responses. We study natively expressed P2X7 receptors, recombinant P2X7 receptors ectopically expressed in various model cell types, and the inflammatory cells derived from P2X7-knockout mice. A current focus is analysis of the signaling mechanisms - and proteins that couple P2X7 receptors to the activation of caspase-family proteases involved in either the maturation of inflammatory cytokines (IL-1b and IL-18) or induction of regulated cell death.
John Feng, Ph.D.,
Assistant Professor of Pharmacology, Member of the Molecular Pharmacology & Cell Regulation Track.
Studies in the Feng laboratory are focused on understanding the molecular and genetic basis of drug addiction. Specifically, the work of Dr. Feng is the first to establish C. elegans as a genetic model for the study of nicotine dependence. He has demonstrated that the behavioral responses to nicotine in worms parallel those observed in mammals, and the genes and pathways regulating nicotine dependence are also conserved between worms and mammals. For example, a conserved gene family identified as novel regulators for nicotine dependence in worms has recently been suggested to be important for nicotine addiction in humans, highlighting the value of using C. elegans as a model for the study of drug dependence. Current studies are aimed at identifying genes that regulate synaptic functions at a genome scale, and screening for compounds that interfere with dopamine neurotransmission in vivo. Dissecting the genetic networks of synaptic transmission is of fundamental importance in neuroscience. Identifying new genes and predicting of their biological functions in synaptic transmission will advance our understanding of synaptic function. Dysfunctions of dopamine neurotransmission are implicated in a variety of diseases such as addiction, Parkinson’s disease, and schizophrenia. Identification of compounds targeting dopamine neurontransmission would lead to the discovery of potential therapeutic drugs for the treatment of these diseases and useful chemical tools for elucidating the mechanisms of dopamine transmission.
Stanton Gerson, M.D., Professor of Medicine and Director of the Comprehensive Cancer Center, member of the Cancer Therapeutics and Translational Therapeutics Tracks.
Dr. Gerson plays an active role in development of new therapeutics as the Associate Director for Clinical Research. His laboratory studies the role of the DNA repair protein O6 alkyguanine-DNA alkyltransferase (AGT) in mediating resistance to several chemotherapeutic agents, and they have led in the discovery and development of the AGT modulator O6benzylguanine as an adjunctive chemotherapeutic agent that enhances the efficacy of DNA alkylating agents. In addition, Dr. Gerson's group has evaluated methoxyamine, an inhibitor of base excision repair, as a potentiator of methylating agent chemotherapy. Studies completed through the NCIRAID and a planned IND submission to pursue a clinical trial of methoxamine and temozolomide for refractory solid tumors are aimed at providing the first agent for inhibition of base excision repair as a therapeutic modality in cancer.
Clifford Harding, M.D., Ph. D., Professor of Pathology, member of the Membrane, Structural Biology & Pharmacology and Translational Therapeutics Tracks.
Antigen processing converts protein antigens to peptide-MHC complexes that can be recognized by T cells. Class I MHC (MHC-I) and class II MHC (MHC-II) molecules are loaded with peptides via two distinct "conventional" processing pathways. MHC-II molecules target to endocytic compartments or phagosomes to bind peptides from exogenous antigens that are cleaved by vacuolar proteases. In contrast, MHC-I molecules are loaded in the endoplasmic reticulum (ER) with peptides that are produced by proteosome cleavage of cytosolic antigens and imported into the ER by TAP. In addition to these "conventional" pathways, The Harding research group is studying "alternate" pathways with different processing mechanisms. Much of their effort is now directed to understanding regulation of antigen presenting cell (APC) function in the context of infectious diseases, e.g. tuberculosis and HIV infection. APCs sense pathogens by innate immune receptors, including Toll-like receptors (TLRs), and are regulated by cytokines and interferons that are produced during infection. For example, they are studying recognition of Mycobacterium tuberculosis by TLRs and the dysregulation of type I interferon responses by APCs from HIV-infected patients.
Charles Hoppel, M.D.,Professor of Pharmacology and Medicine, Chief of Clinical Pharmacology, Director of the Center for Mitochondrial Diseases, member of the Membrane, Structural Biology & Pharmacology and Translational Therapeutics Tracks.
The main focus of the laboratory is mitochondrial fatty acid oxidation. The organization of the pathway for mitochondrial fatty acid oxidation is of particular interest as a potential site for control of the system. Mitochondrial contact sites contain the protein translocases for protein translocation into the mitochondria and the peripheral benzodiazepine receptor. They have data that support the localization of key enzymes, such as the long-chain acyl-CoA synthetase and carnitine palmitoyltransferase of fatty acid oxidation to these contact sites. They have proposed a fatty acidlcarnitine shuttle through the contact sites. The characterization of this shuttle coupled with the determination of its localization within the mitochondria will be essential steps. In addition to the primary basic science focus of the lab which is pertinent to the Membrane Biology Track, Dr. Hoppel's roles as Chief of Clinical Pharmacology and Director of the Mitochondrial Diseases Center put his laboratory at the natural interface of Translational Therapeutics. He oversees many clinical studies aimed at understanding the cell and molecular basis of diseases and devising and testing novel interventions.
Jonathan Karn, Ph. D., Professor and Chair of Molecular Biology & Microbiology, member of the Molecular Pharmacology & Cell Regulation and Translational Therapeutics Tracks.
Dr. Karn joined the CWRU Faculty as Chair of Molecular Biology & Microbiology after spending 22 years at the Laboratory of Molecular Biology at the Medical Research Council (MRC) in Cambridge, England, which is the United Kingdom's equivalent of the NIH. His research on the molecular signals that trigger HIV growth led to the discovery of several novel drug targets and the formation in 1997 of the UK-based, private biotech company Ribo-Targets Ltd. Current research is focused on circumventing the HIV viral defenses against anti-viral agents. If HIV hides in the host cell's DNA in a latent state, existing anti-HIV drugs cannot destroy the virus. In order to flush the virus out so that it can be targeted by drugs, we need to understand the process whereby HIV can be activated. Dr. Karn's group is studying the LTR promoter region of the HIV virus that is responsible for auto-activation of viral replication. They will assess which human and viral proteins transduce signals to the LTR and in which sequence, in order to more fully understand how HIV could be activated as a therapeutic strategy to target otherwise latent virus.
Thomas Kelley, Ph.D.Assistant Professor of Pediatric Pulmonology and Pharmacology, member of the Molecular Pharmacology & Cell Regulation Track.
The research focus of the Kelley laboratory centers around three areas. (1) Identifying a mechanistic link between the loss of CFTR function and altered cell-signaling control in CF airway epithelial cells - Currently efforts are devoted to examination of the isoprenoid/cholesterol synthesis pathway (2) Determining cell signaling consequences of impaired intracellular cholesterol transport - These studies focus primarily on elucidating the consequences of lost NPC1 function in Niemann-Pick type C disease, a pediatric neurological disorder. (3) The regulation of Smad3 expression as a modulator of fibrotic disease - Having observed reduced expression of Smad3 in CF airway epithelial cells, the Kelley lab has pursued studies of regulatory mechanisms that may explain this observation. These studies revealed the potential role of isoprenoids in modification of small GTPase proteins Ras and Rho that in turn may regulate Smad3 signaling. In addition they determined that a protein involved in MAPK activation is essential in maintaining Smad3 promoter function. Identifying other modes of Smad3 promoter regulation and determining methods of modulating the severity of fibrotic diseases by manipulating Smad3 expression are the current objectives of this project.
Ruth Keri, Ph.D.,Assistant Professor of Pharmacology, co-Leader of the Cancer Therapeutics Track, member of the Molecular Pharmacology & Cell Regulation Track.
Research in the Keri laboratory is focused on mechanisms of HER2/Neu and hormonal induction of mammary tumor formation and progression. This has involved the combined used of functional genomics with multiple strains of genetically altered mice. Primary goals of the laboratory are to identify key genes that are regulated by HER2/Neu and mediate the tumorigenic effects of this orphan receptor tyrosine kinase. The protein products of these target genes may then become candidates for therapeutic intervention. One such target is mTOR. We have recently found that an inhibitor of mTOR action, rapamycin, induces regression of HER2/Neu induced mammary tumors in mice. We are currently evaluating the mechanisms for this tumor response as well as examining the impact of rapamycin on metastatic progression.
Timothy Kern, Ph.D., Professor of Medicine and Pharmacology, Director of the Center for Diabetes Research, member of the Translational Therapeutics Track.
The major focus of research in the Kern laboratory is to learn what causes retinopathy in diabetes, and how it can be prevented. Diabetic retinopathy takes many years to develop in most patients, so studies using research animals have been fundamental to our present understanding of this retinopathy. The retinal lesions that develop in experimentally diabetic animals are similar to those that develop in patients, notably including apoptotic degeneration of retinal capillaries. Current studies demonstrate a critical role of inflammatory processes in the development of the retinopathy, and the source and targets of this inflammation are under active investigation using a variety of techniques, including histology, immunohistochemistry, proteomics and bioinformatics, pharmacology, and genetically modified animals.
Irene Lee, Ph.D., Associate Professor of Chemistry, member of the Translational Therapeutics Track.
The goal of the Lee research program is to develop chemical strategies to control cell growth. To this end, we propose to develop a therapeutic cocktail containing agents to inhibit both protein degradation and nucleic acid metabolism. To accomplish this, the Lee laboratory has taken a "rational design" approach to study - enzymes involved in stress-related protein degradation and nucleic acid metabolism. At present, studies focus on the enzymology of an ATP-dependent protease, Lon, which functions to remove damaged proteins and certain short-lived regulatory nucleic acid binding proteins in the cells. In addition, the Lee laboratory is designing and synthesizing non-natural nucleotides to inhibit damaged DNA synthesis mediated by low fidelity polymerases. The overall strategy is to control the growth of an organism by simultaneously inhibiting pathways involved in protein degradation and DNA synthesis.
John Letterio, M.D., Professor of Hematology/Oncology, member of the Cancer Therapeutics and Translational Therapeutics Tracks.
The major focus of the Letterio laboratory is on the discovery of the critical roles of TGF-13 in hematopoietic and immune cell function. The prototype of this family, TGF-131, is expressed by all hematopoietic cell populations, regulates the proliferation and expansion of their progenitors, and plays an important role in controlling various aspects of their development and differentiated functions. Studies in the TGF- 131-1- mouse allowed the Letterio lab to provide the first direct evidence that a TGF-131-deficiency state predisposes to multiple pathogenic manifestations of autoimmunity. Furthermore, endogenous TGF-131 controls developmental expression of both class I and class II MHC antigens, a feature that provide a link between aberrant MHC expression and the inflammation and autoimmunity resulting from TGF-131- deficiency.
Alan Levine, Ph.D., Professor of Medicine and Pharmacology, member of the Molecular Pharmacology & Cell Regulation Track.
The intestinal mucosa is the largest lymphoid organ, as assessed by antibodies produced, resident leukocytes, and surface area exposure to the environment. Further, the wall of the gut is continuously bathed by bacteria, parasites, fungi, amoebae, viruses, mitogens, toxins, and immunogenic food proteins. Therefore, a complex multi-tiered host defense system has evolved in the gut, involving barrier exclusion by an actively regenerating epithelial cell monolayer, innate inflammatory responses mediated by local synthesis of pro- and anti-inflammatory cytokines, and acquired immune responses regulated by T lymphocytes. The Levine Laboratory focuses on the mechanisms that regulate these systems: (1) temporal expression and regulation of pro-inflammatory and anti-inflammatory cytokines in response to gut injury; (2) mechanisms by which co-stimulatory and accessory molecules direct the development of immune tolerance; (3) biochemical, spatial, temporal, and structural organization of the signal transduction pathway initiating with the anti-specific T cell receptor, and differentially regulated in naive, helper, effector, and mucosal T cells; (4) regulation of integrin affinity/avidity, expression, and activation in both nai've and memory T cells by the interstitial extracellular matrix; (5) biochemical signaling pathways emanating from integrin mediated adhesion of intestinal epithelial cells to the basement membrane; and (6) evaluation of a gene targeted murine model of colitis associated colorectal cancer.
Paul N. MacDonald, Ph.D., Associate Professor of Pharmacology, Co-Leader of the Molecular Pharmacology & Cell Regulation Track, member of the Cancer Therapeutics Track.
Vitamin D (Vit D) is required for normal calcium and phosphorus homeostasis and it is essential for the proper development and maintenance of bone. Vit D also exerts profound effects on cellular proliferation and differentiation, effectively inhibiting the proliferation of many tumor-derived, malignant cell lines. The vitamin D endocrine system also profoundly influences normal keratinocyte function and is protective against chemically-induced skin tumorigenesis. The mechanisms underlying its tumor protective and antiproliferative roles are currently unknown. The biological effects of vit D are mediated through a nuclear protein termed the vitamin D receptor, or VDR. The VDR is a member of the superfamily of nuclear receptors that function as ligand-activated transcription factors. Thus, vit D and VDR together regulate the expression of specific genes or gene networks in classic target organs such as the intestine, bone, and skin. The global objective of my laboratory is to understand the molecular details and signaling mechanisms involved in VDR-mediated gene expression. We are currently focusing on in vivo and in vitro models of bone and skin to understand the gene networks that are involved in vit D effects on bone development and skin tumorigenesis.
Danny Manor, Ph.D., Associate Professor of Nutrition, Associate Professor of Pharmacology
Dr. Manor's research interests aim to gain molecular-level answers to basic questions that surround the etiology, treatment and prevention of cancer. Our research interests can be divided to two areas: (1) understanding the signal transduction pathways that regulate normal cell growth and that are disrupted by oncogenic mutations, and, (2) understanding the molecular mechanisms by which some chemo-preventative agents, such as vitamin E, offer protection from cancer ('molecular prevention').
Michael Maguire, Ph.D., Professor of Pharmacology, Co-Leader of the Membrane, Structural Biology & Pharmacology Track, member of the Molecular Pharmacology & Cell RegulationTrack.
Dr. Maguire's laboratory, in collaboration with the Structural Genomics Consortium of the University of Toronto, has recently solved the structure of a closed form of the CorA Mg2+ channel from Thermatoga maritima. CorA is the first divalent cation channel to have it's structure solved. It is a homolog of the mitochondrial Mg2+ channel, Mrs2p. Current work focuses on a) determining the structure of an open form of the CorA channel, b) functional studies on CorA using site-directed mutagenesis, transport assays and electrophysiology, c) the structure of the Mrs2p channel and d) the role of CorA in Salmonella pathogenesis. Further knowledge of the structure/function of Mg2+ transport systems and their role in Mg2+ homeostasis will lead to better understanding of the role of Mg2+ in pathogenesis, mitochondrial function and electrolyte disorders.
Shigemi Matsuyama, Ph.D., Assistant Professor of Medicine-Hematology/Oncology and Pharmacology, member of the Cancer Therapeutics Track.
Dr. Matsuyama studies (1) the molecular mechanism of programmed cell death, and (2) the development of drug-delivery system using cell penetrating peptides. His group found that Ku70 keeps Bax (a key protein inducing apoptosis) at an inactive form in non-apoptotic cells, and that the dissociation of Bax from Ku70 is required for Bax-mediated apoptosis. Ku70 is a ubiquitously expressed protein that has been known to play an important role for double strand DNA brake repair. Dr. Matsuyama's laboratory is investigating how apoptotic stress such as DNA damage modifies Ku701s activity to regulate Bax activity. The understanding of the mechanism of Ku70 modification will contribute the understanding of apoptosis-resistance mechanism of cancer cells. Dr. Matsuyamals laboratory found a new series of cell permeable penta-petides. Dr. Matsuyama's laboratory is investigating the mechanism of membrane penetration by the cell permeable pentapeptides, and the potential application of these peptides for drug delivery into the cell.
John J. Mieyal, Ph.D., Professor and Vice-Chair of Pharmacology, Director of the MTTP, member of the Molecular Pharmacology & Cell Regulation and Membrane, Structural Biology & Pharmacology Tracks.
Recently it has been recognized that reactive oxygen species (ROS) play an important role as second messengers to transduce intracellular signals from hormones, cytokines and growth factors that interact with membrane-associated cell surface receptors. However, little is known about how ROS selectively modify signaling molecules and influence their activation or deactivation, inter-protein interactions, and translocation to the nucleus. Integral to these processes is reversible S-glutathionylation of cysteine residues on specific proteins. Many diseases, including cardiovascular and neurodegenerative diseases, cancer, diabetes, and AIDS, involve oxidative stress conditions that likely disrupt normal redox signaling and alter the balance between cell survival and cell death. Our lab is focused on delineating the enzymatic mechanisms of reversible glutathionylation, and understanding how these link extracellular stimuli to downstream cellular events in health and disease.
Monica Montano, Ph. D., Assistant Professor of Pharmacology, member of the Molecular Pharmacology & Cell Regulation and Cancer Therapeutics Tracks.
The Montano lab studies the role of estrogens in mammary tumorigenesis and the involvement of estrogen receptor (ER) dependent and ER independent pathways. Breast tumor initiation has been proposed to be due to DNA damage attributable to a combination of estrogen metabolism and preexisting lesions. The lab has found that quinone reductase (QR) and ERn inhibit estrogen-induced DNA damage and breast cell transformation. Based on this it is proposed that QR plays a role in mediating the prevention of breast cancer by antiestrogens such as tamoxifen. Another focus is a novel tumor suppressor cloned in the Montano laboratory, hexamethylene-bis-acetamide-inducible protein 1 (HEXIMI). Animal models have been generated that support the role of HEXlMl as a tumor suppressor and anti-angiogenic factor. We have also defined the mechanistic basis for HEXlMl regulation of mammary gland tumorigenesis/angiogenesis.
Noa Noy, PhD., Professor of Pharmacology, co-leader of the Cancer Therapeutics track, member of the Molecular Pharmacology & Cell Regulation Track.
Many lipid-soluble nutrients and hormones regulate cellular behavior by modulating gene expression. These activities are mediated by the ligand-activated transcription factors termed nuclear hormone receptors. Nuclear receptors and their activating hormones thus have profound effects on cell growth, metabolism, differentiation, and death, and they play key roles in numerous pathologies ranging from diabetes to cancer. Work in the Noy laboratory aims to obtain molecular-level understanding of the mechanisms of action of nuclear hormone receptors and their accessory proteins, and to understand the consequences of the activities of these proteins in health and in disease.
Kris Palczewski, Ph.D., Professor and Chair of Pharmacology, Director of the Center for Membrane Biology, Co-Leader of the Membrane, Structural Biology & Pharmacology Track, and member of the Translational Therapeutics Track. The light-sensing apparatus of the eye is found within the rods and cones-two types of specialized cells located in the posterior of the retina. Many unresolved issues relevant to phototransduction, light- and dark-adaptation, and the chemical processing of retinoid cycle intermediates remain unanswered, including the enzymology of the retinoid cycle, the mechanisms by which these intermediates diffuse within and between the photoreceptors and the retinal pigment epithelium, and the dependence of phototransduction reactions on the operation of the cycle. The goals of Professor Palczewski's laboratory are to a) understand the biochemical basis underlying the mechanism of rhodopsin inactivation and restoration of the cGMP level, b) delineate the biochemical basis underpinning the similarities and differences between rod and cone cell phototransduction and c) understand the enzymology of the isomerization of all-trans-retinol to 11-cis-retinol in the retina. Knowledge about phototransduction in the retina, a system with great experimental advantages, will improve further understanding of similar events in hormonal signaling, cellular communication and immune regulation, and provide baseline information for further studies of retinal disease processes.
Susan Redline, M.D., M. P.H., Professor of Pediatrics and Epidemiology and Biostatistics, member of the Translational Therapeutics Track.
Professor Redline's research program is multifaceted with a primary focus on the study of sleep disorders. She heads a Sleep-Heart Health Center that has pioneered approaches for collecting, processing, and analyzing complex polysomnography data and assisted in protocol development, centralized scoring, and quality control for sleep studies to better understand cardiovascular morbidity occurring with sleep apnea. Outcomes of sleep disorders in adolescents is special interest of her research group. This study assesses the prevalence, risk factors, and associated co-morbidity (neurocognitive, behavioral, and metabolic) of sleep disorders in children, ages 13 to 16 years. The study will also determine the rate or progression, and determinants of progression, of sleep disordered breathing from middle childhood through adolescence. Dr. Redline is an important asset to the Advanced Training Track in Translational Therapeutics because of her experience in design and oversight of clinical studies and her expertise in statistical analysis.
Shasta Sabo, Ph.D., Assistant Professor of Pharmacology, member of the Molecular Pharmacology & Cell Regulation Track.
Formation of synapses between CNS neurons is a complex process that establishes the circuits that govern perception and behavior. Despite the importance of proper synapse formation for brain development and function, fundamental questions about the mechanisms of CNS synaptogenesis remain unanswered. For example, how are the protein complexes and specialized membrane domains critical for synaptic transmission assembled at the right place at the right time? How are pre- and post-synaptic assembly coordinated? Are the mechanisms of excitatory and inhibitory synapse formation similar? How is the balance of excitatory and inhibitory inputs onto a neuron controlled? Dr. Sabo’s research aims to address such questions. To study synaptogenesis, Dr. Sabo uses live fluorescence imaging of postnatal rodent cortical neurons. Time-lapse imaging is powerful since it allows simultaneous study of spatial and temporal aspects of synapse formation and permits the observation and manipulation of individual synapses and networks in real-time, as they form. These studies have broad medical relevance since errors in synapse formation can have devastating functional implications: abnormal cortical synaptic connectivity has been linked to diseases as diverse as autism, mental retardation, amblyopia, epilepsy and schizophrenia. Understanding the normal choreography of synaptogenesis will be essential for understanding the etiology of such diseases.
Alvin Schmaier, M.D., Professor of Medicine and Chief of Hematology-Oncology, member of the Translational Therapeutics Track.
Basic research efforts in the Schmaier laboratory examine the influence of the kallikrein/kinin system on vascular biology and its relation to blood pressure regulation and thrombosis. His translational research interests are in anticoagulant development of selective thrombin and thrombin receptor activation antagonists for treatment of cardiovascular disease and cancer. He is the founder and CEO of Thromgen, Inc., Ann Arbor, MI, and currently has an IND study underway.
Gregory Tochtrop, Ph.D.,Assistant Professor of Chemistry, Member, Molecular Pharmacology & Cell Regulation Track and Translational Therapeutics Tracks.
Most biological events emanate from the inherently chemical process of a small molecule being recognized by a large biological polymer. Research projects in the lab are being designed to push back the boundaries of the tools used to monitor protein small molecule interactions. This work spans from pure synthetic organic chemistry to quantitative biochemistry. For example, the pool of bile acids in the human body is chemically heterogeneous, consisting of at least 100 distinct members. One of the major interactions responsible for bile acid homeostasis (and consequently cholesterol homeostasis) is their recognition by the nuclear receptor FXR. The proposed experimental approach is to synthesize 13C and 15N isotopically enriched bile acids and monitor recognition, segregation, and competition using NMR to monitor single bile acids in complex mixtures and understand their effects on the transcription of FXR gene products. Also, the Tochtrop group anticipates building the concept of generating skeletal diversity through chemistries that 'reorganize' the carbon skeletons of compelx natural products into novel molecules. The clevage of the B-C unsaturated ring fusion of lanosterol is a prime example of this strategy. Here, oxidative cleavage of the unsaturated ring fusion followed by transannular addition or full condensation affords diverse skeletons depending partly on the oxidation state of carbons C-7 and C-11. These molecules will be used to probe biological systems using a 'chemical genetic' approach.
Focco van den Akker, Ph.D., Assistant Professor of Biochemistry, member of the Membrane, Structural Biology & Pharmacology Track.
Dr. van den Akker's laboratory is mainly focusing on the natriuretic peptide receptors and related receptors. These receptors are guanylyl cyclase receptors involved in blood pressure regulation and bone growth and their activation leads to the production of the intracellular second messenger cGMP. Determination of the crystal structure of the ligand binding domain of the atrial natriuretic peptide receptor revealed many unexpected discover is such as its structural similarity with periplasmic binding proteins, possible dual allosteric regulation, the hormone binding site, and dimer interfaces. Current projects range from site-directed mutagenesis and activity assays to probe specific mechanistic questions, biochemically characterizing and crystallizing the remaining individual domains, and finally the long term goal of crystallizing the entire receptor which may lead to discovery of new pharmacologically interesting effectors.
Johannes von Lintig, Ph.D., Assistant Professor of Pharmacology, member of the Molecular Pharmacology & Cell Regulation Track.
Dr. von Lintig’s research focuses on the biology of retinoids and their dietary precursors carotenoids. His laboratory recently identified a family of enzymes that catalyze initial steps in the conversion of carotenoids to active vitamin A molecules, i.e. the cis to trans isomerization of caroteinoids, and their oxidative cleavage to retinaldehyde. These findings represent a major breakthrough in the area of retinoid/carotenoid metabolism. A distinctive aspect of Dr. von Lintig’s research is his use of simpler model organisms, specifically Drosophilaand zebrafish for large scale screenings aimed at identifying genes that are relevant to vitamin A biology in mammals. His lab then uses the information that emerges from studies of these organisms to isolate mammalian homologues and establish and characterize corresponding mouse models. This approach has yielded novel insights into physiological functions of carotenoids and retinoids, e.g. the identification of genes that are essential for vitamin A metabolism in the eye. Current work will advance understanding of retinoid and carotenoid metabolism, homeostasis, and function.
Bingcheng Wang , Ph.D., Associate Professor of Medicine-Nephrology, member of the Cancer Therapeutics and Translational Therapeutics Tracks.
The primary interest of the Wang laboratory is understanding the molecular mechanisms governing tumor metastasis, a frequently fatal phase of tumor progression in cancer patients. Agents that can suppress either cell motility or MAPK activity can be exploited to prevent andlor treat metastasis. The Wang laboratory has found that agonists of EphA kinases, including EphAl and EphA2, possess the unique ability to inhibit cell motility and suppress the Ras/MAPK cascade. Current research involves the isolation and characterization of new and more potent agonists of Eph kinases as novel therapeutics to prevent and/or treat tumor metastasis. In addition, the Wang laboratory is searching for small compounds that can bind and modulate Eph kinase function through virtual screening using super computers. Candidate compounds are then tested in vitro and in vivo for anti-cancer activities.
Yu-Chung Yang, Ph.D., Professor of Pharmacology, member of the Cancer Therapeutics and Molecular Pharmacology & Cell Regulation Tracks.
Dr. Yang and her former colleagues at Genetics Institute were responsible for the cloning of three cytokines: human interleukin (IL)-3, -9 and -11. FDA approved IL-I I in 1997 for treating cancer patients with severe chemotherapy-induced thrombocytopenia. It is the first thrombopoietic agent to be approved for clinical use in the United States. They have been interested in studying signaling molecules that may determine cytokine specificity and redundancy. While studying cytokine-dependent signal transduction, Dr. Yang's laboratory cloned Cited2, a transcription factor induced by many biological stimuli and a transforming gene when overexpressed. The laboratory generated Cited2- knockout mice and showed that Cited2-null embryos die at mid-gestation, with defects in heart, lung, liver, eye and hematopoietic development. More recently, the laboratory has also shown that Cited2 is a coactivator of Smads and a negative regulator of HIF-1, is overexpressed in the mammary tumor of MMTV-neu and MMTV-PyvMT transgenic mice and plays an important role in epithelial-mesenchymal transdifferentiation (EMT). Mechanistic studies are underway to study the role of Cited2 in embryonic development and tumorigenesis.
Vivien Yee, Ph.D., Assistant Professor of Biochemistry and Pharmacology, member of the Membrane, Structural Biology & Pharmacology Track.
Dr. Yee's laboratory uses X-ray crystallographic methods to determine and analyze the structures of medically important proteins and of enzymes with interesting mechanistic questions. Her laboratory combines crystallography with modeling and mutagenesis to study several systems. The first of these focuses on serine proteases which are central in blood coagulation, where their interest is in enzyme:substrate peptide structures, to provide some insight into the effect of clinically relevant polymorphisms and into substrate recognition. They are also studying the prion protein, which is implicated in an intriguing family of neurological diseases, the spongiform encephalopathies. Prion protein structures may be helpful in understanding the structural transformation of the protein that is believed to be a key event in the disease. We are also investigating the 1.2 million Dalton transcarboxylase multienzyme complex. Our structures of its large 5s and 12s catalytic subunits serve as models for related mammalian metabolic enzymes, and allow us to speculate on mechanisms and the structural consequences of disease mutations. Finally, in collaboration with the Maguire laboratory, studies are underway on the structure of the CorA Mg2+ channel, specifically to determine the structure of the open form of the channel and the structure of CorA homologs.
Peter A. Zimmerman, Ph.D., Associate Professor, Center for Global Health & Disease, member of the Translational Therapeutics Track.
Research in Dr. Zimmerman's laboratory is focused on understanding the influence of human and parasite genetic polymorphism on infection and pathogenesis of microbial pathogens. This work concentrates on two major intracellular pathogens and their associated diseases: Plasmodium species/malaria and HIV-1/AIDS. Recent studies have uncovered genetic polymorphism in human receptor molecules that malaria parasites and HIV-1 co-opt to facilitate invasion of human erythrocytes and CD4 cells, respectively. Ongoing studies are investigating ways to interfere with biological mechanisms leading to infection as well as the development of agents to block these processes.
