The purpose of this Program Project Grant competitive renewal application entitled """"""""Discovery &Development of Therapeutic Genes for CHF"""""""" is to enable a number of scientists at VMRF and UCSD to maintain an efficient, interactive and mutually reinforcing program of basic and translational research to promote the discovery and development of therapeutic genes for congestive heart failure (CHF) and other cardiovascular diseases. The Program will facilitate the transition from discovery to clinical application of new therapeutic genes. This model combines discovery research with practical """"""""street-smart"""""""" preclinical development. Successfully attaining our goals will require separate but highly integrated Projects that contain the proper proportions f discovery research and focused preclinical development, an accomplished translational physiology Core, and an interactive group of VMRF and UCSD physician-scientists in an ideal environment. Our goals are to identify, perform mechanistic preclinical studies, and eventually to launch clinical trials of promising candidate genes. Strengths of our Program include: i) the breadth of our expertise across disciplines relevant to the goals of the NHLBI;2) the novelty of approaches ranging from bench science to translational studies using high-fidelity animal models of cardiovascular diseases;and 3) our previous success navigating the regulatory pathway from discovery to launching clinical gene therapy trials. Our Program, which is focused on fundamental mechanisms by which the failing heart can be treated (or heart failure avoided), includes three Projects: Project 1 (Dr. Hammond) will develop and test unique AC-related proteins as therapeutic agents for clinical CHF. Project 2 (Dr. Roth) will focus on the impact of cavelolin-3 and mitochondrial function in the pathophysiology and treatment of CHF;and Project 3 (Dr. Dillmann) will use gene transfer to attenuate adverse glycosylation of calcium-related proteins and resolve mitochondrial abnormalities in CHF. Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond).
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