Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

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J.J. JACOBS CENTERFOR THROMBOSIS ANDVASCULAR BIOLOGYJoseph J. Jacobs Center forThrombosis and Vascular BiologyDIRECTOREric J. Topol, M.D.HEAD OF RESEARCHEdward F. Plow, Ph.D.STAFFPaul E. DiCorleto, Ph.D.Joan E.B. Fox, Ph.D.Kandice Kottke-Marchant, Ph.D.ASSOCIATE STAFFKathleen L. Berkner, Ph.D.A. Michael Lincoff, M.D.ASSISTANT STAFFTatiana Byzova, Ph.D.Jane Hoover-Plow, Ph.D.Marc Penn, M.D.STAFF SCIENTISTTatiana Ugarova, Ph.D.PROJECT SCIENTISTSOlga Stenina, Ph.D.Timothy O’Toole, Ph.D.RESEARCH ASSOCIATESKasia Bialkowska, Ph.D.Elzbieta Pluskota, Ph.D.Valentin Yakubenko, Ph.D.POSTDOCTORAL FELLOWSJuhua Chen, Ph.D.Sarmistha De, Ph.D.Bin Hu, Ph.D.Sucheta Kulkarni, Ph.D.Natalia Narizhneva, Ph.D.Prakash Paragi, M.D.Wen Qian, Ph.D.Mark Rishavy, Ph.D.Jingfeng Sha, Ph.D.Aleksey Shchurin, Ph.D.Dmitry Solovjov, Ph.D.Carmen Swaisgood, Ph.D.Valentin Ustinov, Ph.D.Shan Wu, Ph.D.PREDOCTORAL FELLOWNataly Podolnikova, M.S.170The Center for Thrombosis and VascularBiology was founded in 1993 anddedicated in March 1995. Dr. Eric Topol isDirector and Dr. Edward F. Plow is Head ofResearch.The Center comprises 15 faculty membersand has a total staff of 39. Faculty members alsohold appointments in other CCF departments,including the Departments of Cell Biology andMolecular Cardiology in the Lerner ResearchInstitute and the Department of CardiovascularMedicine. The Center is committed to implementinga fully integrated, interdisciplinary approach tothe study of vascular biology and cardiovascularmedicine. Targets of research within the Centerinclude studies of basic molecular and cellularmechanisms, the occurrence and manipulation ofthese mechanisms in animal models, analyses ofthe genes and gene products that play a causativerole in cardiovascular disease and the basis fortheir action, and clinical research in patients, bywhich we seek to better diagnose and improvetherapy for cardiovascular disease.Research programs include studies of theparticipation of platelets in thrombosis andhemostasis. These studies seek to define themolecular basis for the adhesion of platelets to thesubendothelial matrix, to other platelets and toendothelial cells. Critical to platelet adhesion andaggregation are two receptors: integrin α IIbβ 3(GPIIb-IIIa) and GPIb-IX-V. The structure andfunction of these adhesion receptors are beingelucidated using molecular biology, proteinstructure, microscopic imaging, antibody mappingand synthetic peptide approaches. The mechanisms,which regulate activation of the integrinand the signaling events that are induced as aconsequence of ligand binding to both of theseadhesion receptors, are a particular emphasis ofresearch. The ligands for these receptors are beinganalyzed to understand how changes in theirconformation induced by biological events (such asproteolysis, deposition in the extracellular matrix orbinding to other cellular receptors) regulate theirrecognition by their platelet receptors. These basicstudies of platelets are being extended into patientsto determine whether inhibition of these receptorsor other platelet targets can prevent or be used totreat such cardiac diseases as myocardial infarctionsand unstable angina.A similar progression of studies, rangingfrom basic to clinical investigations, occurs in thefibrinolysis/thrombolysis area within the Center.Basic studies of the plasminogen system are beingconducted to identify receptors that regulate theconversion of plasminogen to plasmin and todefine mechanisms that influence the capacity ofplasmin to degrade fibrin. Transgenic mice havebeen developed in which various components ofthe plasminogen system have been inactivated.These transgenic knockout animals are being usednot only to critically evaluate the role of theplasminogen system in fibrinolysis but also to testother postulated functions of plasminogen,including its role in mediating various aspects ofthe inflammatory response and in brain function.At the same time, clinical studies in humanscontinue to compare the efficacy of variousthrombolytic agents in conjunction with othertherapeutic agents to optimize therapy.Our research efforts include analyses ofcardiovascular risk factors, such as fibrinogen andlipoprotein(a), seeking to define the molecular basisfor their pathogenic activities. Such insights maybecome the basis for new diagnostic and therapeuticapproaches. Recent studies of patients haveemphasized the importance of inflammation in thedevelopment of overt cardiovascular disease. Earlyevents in atherosclerosis include the recruitment ofinflammatory cells across the endothelium. Theadhesion receptors that mediate such leukocytetrafficking are the subject of investigation withinthe Center. How receptor activation by physiologicallyrelevant agonists on leukocytes and vascularcells influences the adhesion and migration of thesecells is under intensive investigation.An additional area of emphasis in the Centeris restenosis following angioplasty. Investigators areseeking to identify new molecular targets toprevent neointima formation. Not only new drugsbut also new methods for their delivery are beingtested in a number of different animal models toidentify therapeutic approaches that may beapplicable to limit restenosis in humans. How otherdiseases, such as diabetes, influence the need andoutcome of angioplasty is being evaluated as well.Three areas of emphasis have recently beenadded to the repertoire of research programs in theCenter: (1) A large-scale genetic study conductedin the Center led to the identification of singlenucleotidepolymorphisms (SNPs) within membersof the thrombospondin gene family as risk factorsfor premature atherosclerosis. Studies are beingconducted to determine the effects of thesesubstitutions on the structure and function of thethrombospondins. (2) A promising approach tosalvaging damaged heart tissue is to repopulate itwith progenitor cells that can develop untofunctional cardiomyocytes. Such stem-cell researchhas been initiated to understand, optimize andapply these approaches to patients. (3) Angiogenesis,the formation of new blood vessels, providesa promising approach to restore blood flow todamaged heart tissue. The mechanisms ofangiogenesis and ways to encourage this process arebeing analyzed in vitro and in vivo.Overall, the Center seeks to implement acomprehensive approach to define the basicmolecular mechanisms of cardiovascular diseaseand to extend these insights into new therapies.Web Site: http://www.lerner.ccf.org/tvb/
Center forCancer Drug Discovery and DevelopmentCENTER FOR CANCERDRUG DISCOVERY ANDDEVELOPMENTThe Center for Cancer Drug Discovery andDevelopment, founded in 1998, aims todevelop novel and effective therapeuticoptions for cancer patients. Our intent is todiscover and develop therapeutics with particularfocus on biological agents targeted at genes orgene products that determine the course ofcancer development. We strive to designinnovative approaches to stem the growth andmetastasis of tumors, and our efforts are gearedto translate our findings into rigorous clinicaltrials that test the efficacy of molecular medicalcancer treatments.Lerner Research Institute investigators areadept at discovery, development and evaluationof cancer therapeutics through the targeting ofspecific genes and gene products critical inneoplasia. We aim to translate findings frommolecular biological research into molecularmedical strategies through close collaborationswith investigators at the Cleveland Clinic’s TaussigCancer Center. This molecularapproach to medicine will focuson altering the course of generegulation or deregulation in thebiology of cancer. These novelstrategies offer physicians newapproaches to combat cancer.The Center provides a focusfor investigation of new moleculesin preclinical screeningsystems and to translate theinformation about novel cancerrelatedmolecules to clinical trials.By using the principles ofpharmacology and the knowledgeof cancer biology, we design anddevelop new compounds orcombinations of new compoundsthat reduce morbidity from thecomplications of cancer. Forexample, preclinical and clinicalresearch on new molecules isunder way in collaboration withThe Institute for PathologicalProducts (Shanghai, P.R. China),Igeneon Inc (Vienna, Austria),Immunicon (Philadelphia, PA),Schering-Plough, Inc.(Kenilworth, NJ), and RibozymePharmaceuticals, Inc. (Boulder,CO).We use innovativebiostatistical methodologies toexpedite evaluation of drugtherapies. Our efforts include the development ofonline networks to acquire clinical data for rapid,comprehensive analysis.Our objectives are to develop innovativedrug screening technologies while continuing ourresearch in the design of small molecules targetedat cellular signal transduction. We aim to usenormal programmed cell death (apoptosis) as ameans by which to curtail tumor developmentthrough induction of identified genes. Over thenext few years, new investigators will berecruited for this center to add to existingexpertise.The research community has developed awealth of findings on important cellular processescritical in the regulation of normal proliferationand the initiation, progression and metastasis ofcancer cells. The Center for Cancer DrugDiscovery and Development aims to integrateinformation from these data and use it to developnew approaches to the treatment of cancer.DIRECTORErnest C. Borden, M.D.ASSISTANT STAFFJulian Kim, M.D.Daniel J. Lindner, M.D., Ph.D.Jaroslaw P. Maciejewski,M.D., Ph.D.PROJECT SCIENTISTJoseph A. Bauer, Ph.D.ADMINISTRATORLynn Borzi, M.S.COLLABORATORSG. Thomas Budd, M.D. 1Ronald M. Bukowski, M.D. 1Maurie Markman, M.D. 1Ganes C. Sen, Ph.D. 2Robert H. Silverman, Ph.D. 3George R. Stark, Ph.D. 2Bryan R.G. Williams, Ph.D. 3Yan Xu, Ph.D. 3Taolin Yi, M.D., Ph.D. 3Maciej Zborowski, Ph.D. 41Taussig Cancer Center, CCF2Dept. of Molecular Biology,CCF3Dept. of Cancer Biology,CCF4Dept. of BiomedicalEngineering, CCFErnest C. Borden, M.D.Web Site: http://www.lerner.ccf.org/cancerdrug/171
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