Cardiac Fibrosis Progressive Heart Failure: The Role of Endoglin

心脏纤维化进行性心力衰竭：内皮糖蛋白的作用

基本信息

批准号：
7905732
负责人：
Navin Kumar Kapur
金额：
$ 13.13万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905732
关键词：
Advisory Committees Affect Animals Arts Atherosclerosis Atrial Fibrillation Attenuated Biology Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Cells Chest Clinical Collagen Collagen Type I Congestive Heart Failure Cytokine Receptors Data Development Disease Drosophila Proteins Echocardiography Endoglin Extracellular Signal Regulated Kinases Faculty Feedback Fibroblasts Fibrosis Heart Heart Transplantation Heart failure Homologous Gene Human Individual Instruction Laboratories Ligands Mediating Medical Medical center Medicine Mentors Mitogen-Activated Protein Kinases Modeling Molecular Mothers Mus Myocardial Myocardial Infarction New England Pathway interactions Phenotype Physicians Postdoctoral Fellow Principal Investigator Program Development Proteins Public Health Pulmonary Hypertension Recombinants Relative (related person)Research Research Institute Resources Role Scientist Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Testing Tissues Training Training Programs Transforming Growth Factor beta Universities Work abstracting base career constriction experience gain of function graduate student loss of function medical schools new therapeutic target post-doctoral training pressure prevent professor programs receptor research study translational approach

项目摘要

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)

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发分子心脏病学学术研究职业。首席研究人员在约翰·霍普金斯大学（Johns Hopkins University）在介入心脏病学和心力衰竭/心力衰竭/心脏移植方面完成了心血管医学的博士后培训。该程序将阐明内og的作用，这是心脏纤维化中细胞因子转化生长因子β（TGFB）的共受体的作用。 Michael E. Mendelsohn MD，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领域的公认领导者，是塔夫茨大学医学院分子心脏病学研究所的执行主任，并且已经培训了45多名博士后研究员和研究生。约翰·霍普金斯大学（Johns Hopkins University）的亚伯拉罕（Abraham）和维尔京纳·韦斯（Virgina Weiss）心脏病学教授，戴维·A·卡斯（David A.此外，由备受瞩目的医学科学家组成的咨询委员会将提供科学和职业建议。该研究计划将重点介绍内尾介导的心脏中胶原蛋白合成的抑制作用。 Mendelsohn实验室中的最新工作表明，TGFBL在心脏成纤维细胞中的I型胶原蛋白和内聚糖的表达共激活，而可溶性内聚糖会减弱TGFBL诱导的胶原蛋白合成。提出的实验将使用最先进的分子，细胞和翻译方法来检验以下假设，该假设介导了经典的自动抑制反馈环，该反馈限制了TGFBL诱导的胶原蛋白合成，这是心脏衰竭中心脏纤维化的关键成分。 3个具体目的探索：1）内源是否使用功能的增长和功能方法抑制人类心脏成纤维细胞中TGFB1诱导的胶原蛋白合成，2）2）使用TGFBLBBL诱导的collagin collagin collagin的功能和3）功能的相对依赖性和非依赖性信号途径的相对贡献。压力超负荷引起的野生型和内og型小鼠的心力衰竭（胸腔主动脉收缩）。相关性（请参阅说明）：这些提出的研究具有鉴定内源于内形肽及其调节的信号传导计划，以防止心力衰竭心力衰竭心脏纤维化。塔夫茨新英格兰医学中心的分子心脏病学研究所通过将各种，经验丰富的教职员工和资源的专业知识纳入定制的培训计划中，为培训医师科学家提供了理想的环境。（抽象的结尾）