Cardiac Fibrosis Progressive Heart Failure: The Role of Endoglin

描述(由申请者提供)：本建议书描述了一项为期5年的培训计划，旨在发展分子心脏病学的学术研究生涯。这位首席研究员在约翰·霍普金斯大学完成了心血管医学博士后培训，并在介入心脏病学和心力衰竭/心脏移植方面进行了专业性研究。这个项目将阐明Enoglin，一种细胞因子转化生长因子-β(TGFb)的共同受体，在心脏纤维化中的作用。迈克尔·E·门德尔松医学博士将指导首席研究员的科学发展。门德尔松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研究所的执行主任，培养了45名博士后研究员和研究生。约翰·霍普金斯大学亚伯拉罕和维吉娜·韦斯心脏病学教授、世界知名的心脏重塑专家大卫·A·卡斯医学博士将共同赞助该项目。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。这项研究计划将重点放在内源性激素介导的心脏胶原合成的抑制上。Mendelsohn实验室最近的工作表明，TGFb1共同激活心脏成纤维细胞I型胶原和endoglin的表达，而可溶性endoglin抑制TGFb1诱导的胶原合成。拟议的实验将使用最先进的分子、细胞和翻译方法来测试这一假设，即endoglin介导了一个经典的自我抑制反馈回路，该回路限制了TGFb1诱导的胶原合成，这是心力衰竭中心脏纤维化的关键成分。通过功能获得和功能丧失的方法，探讨endoglin是否抑制TGFb1诱导的人心脏成纤维细胞的胶原合成，2)Smad依赖和独立的信号通路在Enoglin介导的抑制TGFb1诱导的胶原合成中的相对作用，以及3)Enoglin在压力超负荷诱导的心力衰竭(胸主动脉收缩)野生型和Enoglin缺陷小鼠心脏纤维化中的作用。相关性(参见说明书)：这些拟议的研究有可能确定endoglin及其调节的信号程序是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研究所通过将各种经验丰富的教师和资源的专业知识整合到定制的培训计划中，为培训医生和科学家提供了理想的环境。(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)