This proposal describes a 5-year training program for the development of an academic investigative career in Molecular Cardiology. The principal investigator completed post-doctoral training in Cardiovascular Medicine with subspecialization in Interventional Cardiology and Heart Failure/Cardiac Transplantation at Johns Hopkins University. This program will elucidate the role of endoglin, a co-receptor for the cytokine transforming growth factor-beta (TGFb), in cardiac fibrosis. Michael E. Mendelsohn MD, will mentor the principal investigator's scientific development. Dr. Mendelsohn, a recognized leader in the field of cardiovascular biology and cell signaling, is the Executive Director of the Molecular Cardiology Research Institute at Tufts University School of Medicine and has trained more than 45 postdoctoral fellows and graduate students. David A. Kass MD, the Abraham and Virgina Weiss Professor of Cardiology at the Johns Hopkins University and a world-renowned expert in cardiac remodeling, will Co-Sponsor the program. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. This research program will focus on endoglin-mediated inhibition of collagen synthesis in the heart. Recent work in the Mendelsohn laboratory demonstrates that TGFbl coactivates expression of Type I collagen and endoglin in cardiac fibroblasts, while soluble endoglin attenuates TGFbl induced collagen synthesis. The proposed experiments will use state-of-the-art molecular, cellular and translational approaches to test the hypothesis that endoglin mediates a classic auto-inhibitory feedback loop that limits TGFbl-induced collagen synthesis, a key component of cardiac fibrosis in heart failure. The 3 Specific Aims explore: 1) whether endoglin inhibits TGFb1-induced collagen synthesis in human cardiac fibroblasts, using gain of function and loss of function approaches, 2) the relative contributions of Smad- dependent and -independent signal pathways in endoglin-mediated inhibition of TGFbl induced collagen synthesis, and 3) the functional role of endoglin in cardiac fibrosis using a model of pressure overload- induced heart failure (thoracic aortic constriction) in wild-type and endoglin-deficient mice.
These proposed studies have the potential to identify endoglin and the signaling program it regulates as novel therapeutic targets to prevent cardiac fibrosis in heart failure. The Molecular Cardiology Research Institute at Tufts-New England Medical Center provides an ideal setting for training physician-scientists by incorporating the expertise of diverse, experienced faculty and resources into customized training programs.
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