Cardiac Fibrosis Progressive Heart Failure: The Role of Endoglin

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，以发展分子心脏病学的学术研究事业。首席研究员在约翰霍普金斯大学完成心血管医学博士后培训，主修介入心脏病学和心力衰竭/心脏移植。该项目将阐明内啡肽（一种细胞因子转化生长因子- β (TGFb)的共受体）在心脏纤维化中的作用。Michael E. Mendelsohn医学博士将指导首席研究员的科学发展。Mendelsohn博士是心血管生物学和细胞信号领域公认的领导者，是塔夫茨大学医学院分子心脏病学研究所的执行主任，培养了超过45名博士后和研究生。David a . Kass医学博士，约翰霍普金斯大学亚伯拉罕和弗吉尼亚韦斯心脏病学教授，世界知名的心脏重塑专家，将共同赞助该计划。此外，一个由备受尊敬的医学科学家组成的咨询委员会将提供科学和职业建议。这个研究项目将集中在内啡肽介导的心脏胶原合成的抑制。Mendelsohn实验室最近的研究表明，TGFbl在心脏成纤维细胞中共同激活I型胶原和内啡肽的表达，而可溶性内啡肽减弱TGFbl诱导的胶原合成。拟议的实验将使用最先进的分子，细胞和翻译方法来验证内激素介导经典的自抑制反馈回路的假设，该回路限制了tgfb诱导的胶原合成，这是心力衰竭中心脏纤维化的关键组成部分。三个具体目标探讨：1)内啡肽是否抑制tgfb1诱导的人心脏成纤维细胞的胶原合成，通过功能获得和功能丧失的方法；2)内啡肽介导的TGFbl诱导的胶原合成抑制中Smad依赖和独立信号通路的相对贡献；3)内啡肽在野生型和内啡肽缺乏小鼠压力过载诱导的心力衰竭（胸主动脉收缩）模型中的心脏纤维化中的功能作用。相关性（见说明书）：这些拟议的研究有可能确定内啡肽及其调节的信号程序作为预防心力衰竭心脏纤维化的新治疗靶点。塔夫茨-新英格兰医学中心的分子心脏病学研究所为培训医生和科学家提供了一个理想的环境，将不同的专业知识、经验丰富的教师和资源纳入定制的培训计划。（摘要结束）

DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions): 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. (End of Abstract)