Cardiac Fibrosis Progressive Heart Failure: The Role of Endoglin

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展分子心脏病学的学术研究事业。主要研究者在约翰霍普金斯大学完成了心血管医学博士后培训，亚专业为介入心脏病学和心力衰竭/心脏移植。该项目将阐明内皮糖蛋白（细胞因子转化生长因子β（TGF β）的共受体）在心脏纤维化中的作用。Michael E.门德尔松医学博士将指导主要研究者的科学发展。Mendelsohn博士是心血管生物学和细胞信号传导领域公认的领导者，是塔夫茨大学医学院分子心脏病学研究所的执行主任，并培养了超过45名博士后研究员和研究生。大卫A.卡斯医学博士、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。这项研究计划将集中在内皮素介导的抑制胶原蛋白的合成在心脏。Mendelsohn实验室最近的工作表明，TGF β 1共激活心脏成纤维细胞中I型胶原和内皮糖蛋白的表达，而可溶性内皮糖蛋白减弱TGF β 1诱导的胶原合成。所提出的实验将使用最先进的分子、细胞和翻译方法来检验内皮糖蛋白介导经典的自身抑制反馈回路的假设，该反馈回路限制TGF β 1诱导的胶原蛋白合成，这是心力衰竭中心脏纤维化的关键组分。三个具体目标探讨：1）使用功能获得和功能丧失方法，内皮糖蛋白是否抑制人心脏成纤维细胞中TGF β 1诱导的胶原合成，2）Smad依赖性和非依赖性信号通路在内皮糖蛋白介导的TGF β 1诱导的胶原合成抑制中的相对贡献，和3）在野生型和内皮糖蛋白缺陷小鼠中使用压力超负荷诱导的心力衰竭（胸主动脉收缩）模型，内皮糖蛋白在心脏纤维化中的功能作用。相关性（参见说明）：这些拟议的研究有可能确定内皮糖蛋白及其调节的信号传导程序作为新的治疗靶点，以防止心力衰竭中的心脏纤维化。塔夫茨新英格兰医学中心的分子心脏病学研究所通过将多样化，经验丰富的教师和资源的专业知识融入定制的培训计划，为培训医生科学家提供了理想的环境。 (End摘要）

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)