department of pharmacology

Approved Trainers: MTTP



Robert Bonomo, M.D. Professor of Medicine, Pharmacology, and Molecular Biology and Microbiology Professor of Medicine, Pharmacology, and Molecular Biology and Microbiology, Chief of the VA Medical Service, Member of the Translational Therapeutics and Molecular Pharmacology & Cell Regulation Tracks.
Research in the Bonomo laboratory investigates the molecular and clinical aspects of bacterial resistance to beta lactams antibiotics and beta-lactamase inhibitors. The main areas involves understanding the structure function relationships of the class A beta-lactamases, SHV-1 and KPC-2. These chromosomal and plasmid encoded beta-lactamase confers high level resistance to cephalosporins and carbapenems, which can render ineffective the most frequently used drugs to treat serious nosocomial infections. Dr. Bonomo also has projects studying OXA carbapenemases found in Acinetobacter baumannii, the cephalosporinase of Pseudomonas aeruginosa, the class A beta-lactamase of Mycobacterium tuberculosis, and metallo-beta-lactamase, NDM-1. The lab also is studying the bacterial membrane proteins, transpeptidases and carboxypeptidases, involved in cell wall synthesis. A major effort also involves rapid molecular diagnostics and typing.

Matthias Buck, Ph.D. Professor of Physiology & Biophysics and Pharmacology, 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 with a concentration on the plexin and the Eph-A1 and Eph-B1 transmembrane receptors. Protein interactions determine the basic mechanisms by which proteins transmit signals in cells and how signal-ing is disrupted by mutation in diseased states. Knowing at near-atomic resolution which residues interact in protein complex formation will allow them to rationalize their interaction affinity and specificity. Furthermore, it will provide an opportunity for them to alter the proteins for diagnostic or therapeutic purposes. Both plexin and Eph receptor 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.

Chris Dealwis, Ph.D. Associate Professor 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. Their approach is to use a multidisciplinary cycle to study the structure-function relationship of proteins. They also use structure-based drug and protein design to develop novel therapeutics against cancer, Alzheimer’s disease and microbial infections. These biophysical studies are facilitated by tech-niques such as X-ray & neutron crystallography; molecular modeling; CD, MS, and fluorescence spectroscopy; and ultracentrifugation.

Analisa DiFeo, Assistant Professor of Oncology, Member of the Cancer Therapeutics Track.
Chemotherapy resistance and tumor recurrence are common in women diagnosed with high-grade epithelial ovarian cancer. Researchers have been unable to predict patient response to therapy because they do not have a thorough understanding of the complex mechanism within the tumor that causes drug resistance and recurrence. Dr. DiFeo’s laboratory is focused on identifying genetic aberrations that are critical for the develop-ment of drug resistance and ovarian cancer progression. These genetic changes will ultimately serve as novel biomarkers of the therapeutic responses to typical chemotherapy of ovarian cancer and/or to innovative targeted molecular therapies that can work alone or in conjunction with current treatment options to combat ovarian cancer. Using a combination of in vitro and in vivo approaches, we strive to better understand the mechanism by which both microRNA’s and the genes they regulate are involved in ovarian tumor biology and chemoresistance at the cellular level as well as in disease development and progression in animals.

Stanton Gerson, M.D. Professor of Medicine, Director of the Comprehensive Cancer Center Professor of Medicine, 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 develop-ment of the AGT modulator O6benzylguanine as an adjunctive chemotherapeutic agent that enhances the effi-cacy 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 NCI-RAID 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, Interim Chair of Pathology Professor and Chair of Pathology, Member of the Membrane Structural Biology & Pharmacology and Translational Therapeutics Tracks.
Dr. Harding’s research is focused on topics in immunology, particularly functions of antigen presenting cells, including: 1. Antigen presentation by MHC molecules. 2. Phagosomal processing of antigens, including MHC-I cross processing mechanisms that contribute to immune responses to tumors and pathogens. 3. Regulation of antigen presenting cells and T cell responses by signaling by Toll-like receptors, including TLR9 and TLR2. 4. Induction of type I interferon by Toll-like receptors, particularly TLR9, and its role in induction of MHC-I cross presentation. 5. Inhibition of type I interferon induction by TLR2 signaling and by CpG-B agonists of TLR9. 6. Antigen presenting cell dysfunction in infection by Mycobacterium tuberculosis or HIV and the roles of abnormal Toll-like receptor or interferon responses in these mechanisms.

Yoshikazu Imanishi, Ph.D. Associate Professor
Director of Light Microscopy Imaging Core Assistant Professor of Pharmacology, Member of the Membrane Structural Biology & Pharmacology Track.

The Imanishi lab is focused on localization of proteins and chemical intermediates involved in phototransduction and the visual cycle using modern imaging techniques, such as two-photon microscopy. They are interested in how these highly specialized neurons are formed and maintained, and how the major component of the outer segment, rhodopsin, can contribute to the formation of the photoreceptor outer segments. The maintenances of photoreceptor outer segments are subject to regulation by circadian rhythm; however the underlying mechanism is currently unknown. The interactions between photoreceptors and adjacent Retinal Pigment Epithelial (RPE) cells are required for normal metabolism and maintenance of photoreceptor cells. RPE cells retain unique biological functions; RPE cells are the most active phagocyte throughout the body, and this activity is responsible for the maintenance of photoreceptor outer segments. Current research addresses how the RPE and the photoreceptor communicate with each other to orchestrate the biogenesis and degradation of photore-ceptor outer segment structure.

Ruth Keri, Ph.D. Professor and Vice Chair
Department of Pharmacology
Associate Director for Basic Research
Case Comprehensive Cancer Center Professor and Vice Chair of Pharmacology, co-Director of the MTTP, co-Leader of the Cancer Therapeutics Track, member of the Molecular Pharmacology & Cell Regulation Track.

The Keri laboratory is focused on mechanisms of HER21Neu 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 HER21Neu 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. The Keri group has recently found that an inhibitor of mTOR action, rapamycin, induces regression of HER21Neu induced mammary tumors in mice. They 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
Director of the Center for Diabetes Research Professor of Medicine, 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 present understanding of this problem. The retinal lesions that develop in streptozotocin-diabetic animals are indistinguishable from those that develop in patients, and include microaneurysms, obliterated capillaries, pericyte loss and hemorrhage. The Kern group has also developed a second model of diabetic retinopathy in which blood hexose levels are elevated in nondiabetic animals by feed-ing the sugar, galactose. These animals develop a retinopathy identical to that which develops in diabetes, in-dicating that elevated blood hexose is a major cause of diabetic retinopathy. Efforts currently are directed at identifying how hyperglycemia causes retinopathy, so that new, improved treatment may be devised to inhibit the loss of vision in diabetes.

Alan Levine, Ph.D. Professor Professor of Pathology 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. Furthermore, the wall of the intestine 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 intestine, 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 and immunoregulatory mediators in response to mucosal inflammation; (2) mechanisms by which co-stimulatory molecules and environmental stimuli direct the de-velopment 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 naive and memory T cells by the interstitial extracellular matrix; (5) evaluation of a gene targeted murine model of coli-tis-associated colorectal cancer; and (6) mechanisms for increased intestinal permeability induced by HIV infec-tion and/or exposure to drugs of abuse, such as opioids, methamphetamine, and cocaine.

Stephen J. Lewis, Ph.D.Professor of Pediatrics Member of the Molecular Pharmacology and Cell Regulation Track
The major focus of the Lewis laboratory is to understand the mechanisms by which endogenous thiols (e.g., cysteine, cysteamine and glutathione) and S-nitrosothiols (e.g., S-nitrosocysteine, S-nitrosocysteamine and S-nitrosoglutathione) as well as their synthesis and degradation pathways influence the central and peripheral regulation of microcirculatory and ventilatory systems in rats and mice under physiological and pathophysiological settings. The laboratory uses a multi-disciplinary approach ranging from whole animal physiology and pharmacology to electrophysiology (e.g., whole fiber neural recordings, single cell patch clamping) to cell/molecular biology (e.g., Western blot, RT-PCR). One current project focuses on our findings in conscious rats and mice that systemic injections of novel S-nitrosothiols and disulfides (1) stimulate minute ventilation, (2) prevent disordered breathing (e.g., apneas, sighs, sniff) in models of sleep apnea, and (3) reverse the deleterious effects of opioids on minute ventilation, arterial blood-gas chemistry, and alveolar gas-exchange without negatively affecting the analgesic actions of the opioids. We are currently evaluating select S-nitrosothiols and disulfides as potential therapeutics for the improvement of ventilatory and hemodynamic function in human disease states (e.g., sleep apnea, sepsis) and to combat opioid-induced respiratory depression.

Shigemi Matsuyama, Ph.D Associate Professor, Medicine Associate Professor of Medicine-Hematology/Oncology, Member of the Cancer Therapeutics Track.
Dr. Matsuyama studies (1) the molecular mechanism of programmed cell death, and (2) the development of a drug-delivery system using cell penetrating peptides. His group found that Ku70 keeps Bax (a key protein in-ducing apoptosis) in an inactive form in non-apoptotic cells, and that the dissociation of Bax from Ku70 is re-quired for Bax-mediated apoptosis. Ku70 is a ubiquitously expressed protein that has been known to play an important role for double strand DNA break repair. Dr. Matsuyama's laboratory is investigating how apoptotic stress such as DNA damage modifies Ku70’s activity to regulate Bax activity. The understanding of the mecha-nism of Ku70 modification will contribute to understanding apoptosis-resistance mechanisms of cancer cells. Dr. Matsuyama’s laboratory found a new series of cell permeable pentapeptides and is investigating the mechanism of membrane penetration by these pentapeptides, and the potential application of these peptides for drug delivery into cells.

Jason Mears, Ph.D. Assistant Professor Assistant Professor of Pharmacology, Member of the Membrane Structural Biology & Pharmacology Track.
Within eukaryotic cells, mitochondria continually divide and fuse. Defects in these processes are associated with an increasing number of human diseases, including cancer, neurodegeneration and aging. Research in the Mears lab is focused on understanding of the cellular machinery that regulates mitochondrial dynamics in yeast and mammalian cells. They use cryo-electron microscopy along with biochemical and computational methods to elucidate the structural and mechanistic roles of proteins in the eukaryotic fission machinery.

Goutham Narla, M.D., Ph.D. Assistant Professor of Medicine, co-Leader of the Translational Therapeutics Track and Member of the Cancer Therapeutics Track.
Research in the Narla laboratory focuses on the understanding of the molecular mechanisms underlying the inactivation of tumor suppressor genes in human cancer. The main areas of research focus are the development and validation of small molecule based therapies to reactivate key negative regulators of oncogenic signaling, mainly protein phosphatases (PP2A), in disease relevant cell culture and mouse models of cancer. Additional areas of research focus in the laboratory include understanding at the genomic and proteomic level how perturbations in transcription factor and protein phosphatase function perturb signaling in cell culture and in vivo models. In addition, comprehensive molecular characterization of these disease relevant drivers of tumor development and progression in human tumor samples is an area of research focus in the laboratory. The ultimate goal of these studies is the clinical translation of these small molecule based approaches to the treatment of a broad range of human cancers.

Marvin Nieman, Ph.D. Associate Professor Assistant Professor of Pharmacology, co-Leader of the Translational Therapeutics Track.
The underlying research theme of the Nieman lab is that protease activated receptor (PAR) subtypes interact with one another to mediate the full range of thrombin signaling for activation of platelets, endothelial cells and mononuclear cells. Thrombin is the terminal enzyme in the clotting cascade that activates cells by cleaving PARs. PAR1 and PAR4 interact on the platelet surface and PAR1 enhances PAR4 activation ~10-fold by serv-ing as a cofactor. In other tissues and cell types, PAR1 interacts with and transactivates PAR2. Therefore, studies examining thrombin signaling must take into account contributions of other PARs expressed by the cells of interest. The Nieman lab uses a combination of enzyme kinetics, resonance energy transfer, cell based as-says with cell lines and freshly isolated human and mouse platelets as well as animal models to examine the influence of the interaction of PAR subtypes on thrombin signaling with the aim of discovering new therapeutic approaches to controlling blood clotting.

Krzysztof Palczewski, Ph.D. Professor and Department Chair Professor and Chair of Pharmacology, and Member of the Membrane Structural Biology & Pharmacology and Translational Therapeutics Tracks.
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 fundamental information for therapeutic interventions and further studies of retinal disease processes.

Paul Park, Ph.D. Assistant Professor Assistant Professor of Ophthalmology and Pharmacology, Member of the Molecular Pharmacology & Cell Regulation and Membrane Structural Biology & Pharmacology Tracks.
The goal of the Park laboratory is to understand the mechanisms of signal transmission at the molecular level in phototransduction and other G protein-coupled receptor-mediated signaling systems. The specific aims of the research include: 1) to test the validity of assumptions in classical schemes of signaling and to explore more recent paradigms of signal transmission; 2) develop and characterize methodologies to detect and monitor mo-lecular interactions involving receptors; 3) develop and characterize tools that will allow for live cell and/or in vivo monitoring of signaling events; 4) to understand at a molecular level how mutations in rhodopsin lead to vision-related disorders. The Park lab uses modern biophysical approaches to tackle these issues, including atomic force microscopy (AFM), single-molecule force spectroscopy (SMFS), and fluorescence-based methods.

Irina Pikuleva, Ph.D. Professor Professor of Ophthalmology and Pharmacology, Member of the Molecular Pharmacology & Cell Regulation and Membrane Structural Biology & Pharmacology Tracks.
Cholesterol is essential for life in mammals. However, if chronically in excess, it becomes a risk factor for cardiovascular and Alzheimer’s diseases, and possibly age-related macular degeneration. The focus of this la-boratory is on the four cytochrome P450 enzymes 7A1, 27A1, 46A1, and 11A1 that are necessary for choles-terol elimination from different organs. They are striving to understand how cholesterol-metabolizing P450s function at the molecular level, what roles they play in the development of different diseases, and whether these enzymes could serve as targets for cholesterol lowering medications. One of the current projects is based on previous structural and biochemical studies of CYP46A1, showing that the enzyme active site is conformational-ly flexible and can accommodate ligands other than sterols. The goal of this project is to identify marketed drugs that can either inhibit or stimulate the CYP46A1-mediated cholesterol hydroxylation in vivo. Another project is focused on understanding how deactivation of the CYP27A1 enzyme under oxidative-stress may alter cholesterol metabolism and contribute to age-dependent macular degeneration. In pursuit of these goals, the lab uses in-silico and in vitro screening of drug libraries, X-ray crystallography, mass spectrometry, and tests on animals.

William Schiemann, Ph.D Associate Professor
Leader of the Breast Cancer Program of the Case Comprehensive Cancer Center Associate Professor of Oncology, Leader of the Breast Cancer Program of the Case Comprehensive Cancer Center, co-Leader of the Cancer Therapeutics Track.

Tumorigenesis elicits changes in the TGF-beta signaling pathway that engenders resistance to the normally cytostatic activities of TGF-beta, thereby enhancing the development and progression of human malignancies. These genetic and epigenetic events convert TGF-beta from a suppressor of tumor formation to a promoter of their growth, invasion and metastasis. The dichotomous nature of TGF-beta during tumorigenesis is known as the “TGF-beta paradox.” Dr. Schiemann's research aims to understand the molecular mechanisms underlying the "TGF-beta Paradox" – likely the most important unanswered question concerning the pathophysiological functions of this multifunctional cytokine in regulating mammary tumorigenesis. Particular focus is on the initia-tion of metastasis and disease recurrence. The Schiemann group has made numerous and highly significant contributions toward answering this important question, and in doing so, has established new insights into the molecular mechanisms underlying the TGF-beta Paradox and its ability to influence the response of normal and malignant mammary tissues to TGF-beta.

Phoebe L. Stewart, Ph.D. Director, Cleveland Center for Membrane and Structural Biology Professor, Department of Pharmacology Case Western Reserve University Professor of Pharmacology, Director of the Cleveland Center for Membrane and Structural Biology, Co-Director of the MTTP, and Member of the Membrane and Structural Biology and Pharmacology Track.
Cryo-electron microscopy (cryo-EM) plays a central role in hybrid methods to determine structures of mem-brane proteins and large complexes in multiple conformations without the need for crystals. Docking of atomic resolution structures and computational models into cryo-EM density maps can provide insight at the near-atomic level. The Stewart lab is applying cryo-EM structural methods to a variety of adenovirus/host factor com-plexes, including defensin and coagulation Factor X. Adenovirus is a common human pathogen, but non-virulent forms have shown great potential for gene delivery and vaccination strategies. When adenovirus is injected intravenously, however, it induces potent innate immune and inflammatory responses, the molecular basis for which remains poorly characterized. Human defensin 5 is a peptide from the innate immune system that blocks viral cell entry. Factor X plays a role in the blood coagulation cascade and leads to highly efficient adenoviral infection of hepatocytes. Thus, elucidating the molecular interactions of these key adenoviral complexes is expected to lead to improved therapeutic approaches with adenoviral vectors. In addition, the Stewart group is studying protein/DNA complexes involved in nonhomologous end joining (NHEJ) and in maintenance of cir-cadian rhythm. DNA damage is a natural occurrence, but If the damage is not repaired correctly, genetic insta-bility may result and lead to cancer or cell death. The human DNA-PKcs enzyme mitigates oncogenesis through NHEJ repair of double strand DNA breaks. Circadian rhythms impact cellular and organismal physiology, regu-lating sleep cycles, as well as hormone and metabolic activities. In both the DNA repair and circadian rhythm systems, cryo-EM provides a way to study the structure of large and conformationally flexible complexes.

Derek Taylor, Ph.D. Associate Professor Assistant Professor of Pharmacology, Director of MTTP Admissions, Member of the Membrane Structural Biology and Pharmacology Track
Regulation and deregulation of gene expression are critical events for every process within the cell. Alteration of these intricate processes, for example as consequences of genetic defects or bacterial/viral infections, can readily lead to one of many human ailments. The control of these processes is commonly modulated by multi-protein complexes; in fact, proteins rarely act alone, but interact intimately and precisely with other proteins and nucleic acids to properly perform their cellular functions. The Taylor laboratory studies the structure and molecular mechanisms of macromolecular machines involved in DNA maintenance and RNA maturation and biogenesis. They use cryo-electron microscopy and single particle reconstruction techniques as primary tools for visualizing the macromolecular complexes in order to better understand their functions.

Johannes von Lintig, Ph.D. Associate Professor with Tenure, Pharmacology Associate Professor of Pharmacology, Member of the Molecular Pharmacology & Cell Regulation Track.
Carotenoids affect a rich variety of physiological processes in nature and are beneficial for human health, serving as free radical scavengers and filters of phototoxic blue light. These isoprenoid pigments also serve as precursors for retinoids (vitamin A and its derivatives) that are essential for vision, cell proliferation, and embry-onic development. Recently, molecular players in this pathway have been identified and biochemically charac-terized. Mutations in the corresponding genes induce various pathologies in humans, including blindness and the fatal Matthew Wood syndrome. The von Lintig research group has established homologous animal models to study the mechanistic basis of these diseases. The biological studies are accompanied by in vitro struc-ture/function analyses of key proteins of these pathways. By defining a detailed molecular framework of carot-enoid metabolism in health and disease, the research team believes that improved pharmacological agents can be designed and developed to combat and prevent diseases associated with carotenoid metabolism.

Bingcheng Wang, Ph.D. Professor Professor of Medicine-Nephrology and Pharmacology, Member of the Cancer Therapeutics and Translational Therapeutics Tracks.
The Wang laboratory is interested in the molecular mechanisms driving invasive and metastatic tumor pro-gression responsible for most cancer-related mortality. Their research is focused on Eph receptor tyrosine ki-nases that have been known as essential guidance molecules of cell migration during embryonic development. Studies in the Wang laboratory demonstrate that Eph kinases also critically regulate tumor cell migration and invasion via crosstalk with integrins, Ras/ERK and PI3K/Akt pathways (Nature Cell Biology 3:527, 2001; Cancer Cell 16:9, 2009). The mechanistic insights laid a foundation for the ongoing translational research devoted to the isolation and characterization of small molecules targeting Eph kinases. Multiple lead compounds have been found that could bind Eph kinases and inhibit both Ras/ERK and PI3K/Akt signaling cascades. Preclinical studies are underway to develop the lead compounds into novel therapeutics against tumor dissemination using mouse models of glioma and prostate cancer.

Youwei Zhang, Ph.D. Associate Professor Assistant Professor of Pharmacology, Member of the Cancer Therapeutics Track.
Eukaryotic cells have evolved an elaborate network of genome surveillance and repair machinery to insure that DNA replication occurs in an accurate and timely fashion. This surveillance mechanism is termed the S-phase replication checkpoint. The replication checkpoint monitors the progress of replication forks, and when the fork stalls, transmits signals that delay S-phase progression, and maintain the stability of stalled forks so that DNA replication can resume after the initial error is corrected. Two key components of the replication checkpoint are the apical protein kinase, ATR, and its downstream target kinase, Chk1. Replicative stress induces activation of ATR, which then induces activation of Chk1 through phosphorylation at Ser317 and Ser345. Activated Chk1 will activate a cascade of downstream effectors, which will eventually induce cell cycle arrest and damage repair to maintain cell survival, or cell death if the damage is too severe to be repaired. Dr. Zhang’s research group is interested in dissecting the detailed molecular mechanisms underlying the activation of the replication checkpoint, and translating that knowledge into potential anticancer treatment.

Richard Zigmond, Professor of Neurosciences, Member of the Molecular Pharmacology & Cell Regulation Track.
Dr. Zigmond's lab focuses on adaptive responses of adult neuron's to injury. Due to their suitability for a variety of experimental approaches and to their ability to regenerate after injury, our studies involve the peripheral nervous system, using both sensory and sympathetic neurons. We have two current goals. The first is to examine the mechanisms underlying our recent finding that macrophages enter into peripheral sensory and sympathetic ganglia after axonal damage and promote nerve regeneration. The second is to examine the biochemical changes that underlie diabetic neuropathy. In these latter studies, we are concentrating on our previous findings establishing a role for gp130 cytokines in nerve regeneration and our recent findings that this signaling system is dysregulated in diabetes.