The purpose of this Program is to form efficient, interactive and mutually reinforcing program of basic, translational and clinical research in cardiovascular gene therapy. Our overriding goal is to translate basic bench discoveries in cardiovascular diseases into disorders affecting the heart is feasible but will require a multi-disciplinary approach with a global examination of new gene transfer and deleterious effects of transgenes to minimize potential and rigorous implementation of human clinical studies. We have brought together a group of leading basic, translational and clinical establishment of this new Program, the strong basic and clinical research environment at UCSD, and the historical and ongoing activities in gene therapy at this university will provide a superb environment to take a comprehensive and rigorous collaborations among scientists, provide them with high quality reagents, tools and services and promote the rapid translation of research in cardiovascular gene therapy. Dr. Hammond, the PI of the Program, will initiate a clinical trial in patients with severe heart failure (Project 1) using intracoronary (non- surgical) delivery of an adenovirus encoding Type VIII adenylyl cyclase to increase data supporting this approach over the last 5 years, and recently demonstrated the safety and efficacy of intracoronary gene transfer of adenovirus in treating human patients in a Phase I/Phase 2 blinded, placebo-controlled clinical trial. Other Projects will examine the effects of gene transfer on cardiovascular function and structure using in vitro and in vivo models. These studies are directed to obtain data supporting additional gene therapy studies. Other Projects are intended to facilitate gene transfer by providing high quality vectors (Core B), gene targeting to the cardiovascular system (Project 3), and the effects of gene transfer on cellular structure and function (multiple Projects with Core A). DR. Insel (Project 2) will transfect pulmonary artery smooth muscle cells with isoforms of adenylyl cyclase to alter signaling-exploring the potential for gene transfer in treating pulmonary hypertension. Dr. Friedmann (Project 3) will examine the in vivo fate of retrovirus and lentivirus vectors after systemic delivery, examining host immune responses. He also will use phage display libraries to identify tissue- targeting peptides for vector targeting, strategy that will be useful to multiple projects. Dr. Witztum (Project 4) will use gene transfer to arrest progression of atherosclerosis-vectors encoding single chain antibodies will be targeted against "oxidation-specific" epitopes of extracellular oxidized LDL. In summary, this Program will establish a comprehensive and rigorous program in translational research and clinical cardiovascular gene therapy.