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

The Department of Molecular CardiologyContinued from Page 118natriuretic factor and its receptor at a structurallevel. This ligand-receptor system is believed toplay a central role in the heart failure response.ThrombosisThrombosis remains the leading cause ofdeath in the United States. A better understandingof the molecular mechanisms of thrombosis,hemostasis and fibrinolysis represents a third area ofresearch, emphasized within several laboratories inthe department. The laboratory of Dr. Plow isinterested in the function of the components ofthe plasminogen system, the molecular pathwaythat is responsible for the dissolution of blood clotsand a system that also influences cell migration. Hisstudies use mice in which the genes for variouscomponents of the plasminogen system have beeninactivated, and these knockout mice provide ameans to dissect the role of the plasminogen systemin physiologic and pathophysiologic events.Essential to the function of blood coagulationproteins is their post-translational modification byγ-carboxylation. Dr. Berkner’s lab seeks to definethe regulation of this event and to characterize theresponsible γ-carboxylase. The laboratories of Drs.J. Fox and Plow have major research effortsfocused on the role of platelets in thrombusformation. The receptors that mediate plateletadhesion and aggregation, events that are central tothrombus formation, are under analysis. Dr.Byzova’s laboratory investigates how particularsignaling molecules and events control plateletadhesive responses. Her studies utilize transgenicmouse models to dissect the contributions of thesesignaling molecules.Vascular BiologyVascular biology, the department’s fourtharea of emphasis, is broadly studied throughout theLerner Research Institute. Cell adhesion, intracellularsignaling events and pathways and regulation ofthe cytoskeleton represent specific cellular processesthat contribute to complex physiologic andpathophysiologic responses, such as angiogenesis,atherosclerosis and restenosis. Cell adhesionmechanisms are major areas of emphasis within thelaboratories of Drs. J. Fox and Plow. Studies ofligand binding to integrin adhesion receptors andactivation of these adhesion receptors are majortopics of investigation. Dr. Qin, a structuralbiologist (see below), uses NMR to study thestructural basis for integrin activation and celladhesion. A major focus of research in Dr. Byzova’slaboratory is angiogenesis; in vitro and in vivo modelsare utilized to study how growth factors induce thisresponse. Together, these laboratories seek to gaininsights into the processes underlying atherosclerosis,restenosis, and therapies for these diseases.Downstream signaling events and cytoskeletallinkages triggered by activation and occupancy ofthese receptors are areas of intense investigation.Genetic Basis of Cardiovascular DiseaseThe genetic basis of cardiovascular diseasehas evolved into a major theme of research in theDepartment. Dr. Wang’s laboratory is seeking toidentify mutations in genes that cause cardiacarrhythmias and vascular abnormalities in humansand then develops animal and cellular models todetermine how these mutations lead to the abnormalphenotypes. Dr. Topol has organized largemulticenter studies to identify allelic variantsinvolved in premature coronary artery disease andmyocardial infarction. These studies have spurredcollaborations with Dr Wang to find the genesleading to these cardiovascular diseases and withDrs. Plow and Byzova to determine why a singlenucleotide polymorphism in a particular family ofproteins is associated with an increased risk ofcoronary artery disease. Dr Karnik is seeking toidentify polymorphisms within an angiotensinreceptor gene and how these are linked to cardiovasculardisease. Dr. Bond uses gene chip analyses toidentify genes that are altered in human failing hearttissues, to determine if gene expression patterns canbe used to predict the course of heat failure, and toidentify molecular targets that may have a causativerole. Many analyses in the Department involve theuse of transgenic mice in which gene products areoverexpressed or inactivated to dissect how specificproteins known to contribute to cardiovasculardisease exert their functions.Structural BiologyThe above synopsis of ongoing researchactivities within the Department of MolecularCardiology indicates a heavy emphasis on peptideand protein functional analyses. To complementthese endeavors, Dr. Qin, a structural biologist,who studies basic aspects of protein structure andfunction and represent the fifth area of researchemphasis in the Department. Dr. Qin usesnuclear magnetic resonance spectroscopy toanalyze the three-dimensional structure of a widevariety of proteins. Together with facultymembers in various departments throughout theLerner Research Institute, Dr. Qin is a member ofa growing body of structural biologists withinCleveland’s structural biology community, whoseek to bring these state-of-the-art approaches toprovide high resolution understanding of howprotein molecules work. Knowledge of thethree-dimensional structure of proteins not onlyprovides insights into their modus operandi but alsois key to the future of drug design to target theseproblems.Dept. website: http://www.lerner.ccf.org/moleccard/119