The role of the BMP type II receptor in vascular function

描述(由申请人提供)： 这项拟议的研究检查了骨形态发生蛋白(BMP)信号在血管系统中的功能。以往的研究已经证实了BMP信号对血管内皮细胞和平滑肌细胞功能的影响，表明BMP信号是血管分支和重塑的重要调节因子。BMP信号的主要受体BMP II型受体(BMPR2)的功能缺失突变与血管病理性疾病原发性肺动脉高压有关，进一步支持了在血管功能中的重要作用。然而，BMP信号调节血管组织功能的机制还不完全清楚。使用Cre-lox系统和转基因小鼠可以在体内和体外对BMPR2基因进行组织特异性破坏。我们将研究BMPR2信号对血管细胞功能和转录活性的影响，以及可能的影响机制。细胞生理学将利用肺血管血流动力学功能、结构和发育的终点，在体内与破坏BMPR2的影响相关。这些研究将有助于确定BMPR2和BMP信号在正常和病理血管功能中的作用，并可能提供肺动脉高压的动物模型。研究计划的完成和所需技能和经验的获得将为作为一名专门从事心脏和肺血管生物学的内科科学家的职业发展奠定坚实的基础。这位首席研究员正在从奖学金培训过渡到马萨诸塞州总医院心脏科的教员，并建议扩展他在分子遗传学、细胞生物学和动物生理学方面的科学技能，以促进向独立研究员的过渡，成为一名熟练于整合疾病的分子和生理方面的研究人员。职业发展计划包括由有成就的科学家组成的咨询委员会提供科学和职业指导；参加相关的研讨会、课程和国家会议；以及提供受保护的研究时间。该提案将利用当地广泛的技术专长和马萨诸塞州综合医院目前高度合作的环境。与健康相关：骨形态发生蛋白被细胞用来协调新组织的生长和维持现有组织，在发展和维持正常血管方面尤其重要。这项研究考察了骨形态发生蛋白受体(BMPR2)如何协调血管细胞的功能，以及BMPR2的功能异常如何导致循环障碍。(摘要结束)

DESCRIPTION (provided by applicant): The proposed research examines the function of bone morphogenetic protein (BMP) signaling in the vasculature. Previous work in the field has demonstrated the impact of BMP signals upon the function of vascular endothelial and smooth muscle cells, indicating that BMP signals are important regulators of vessel brmation and remodeling. Loss-of-function mutations in the principal receptor for BMP signals, the BMP type II receptor (BMPR2) are implicated in the vasculopathic disease primary pulmonary hypertension, further supporting an essential role in vascular function. However, the mechanisms by which BMP signals modify the function of vascular tissues are incompletely defined. Use of the Cre-lox system and genetically modified mice has permitted tissue-specific disruption of the BMPR2 gene in vivo and in vitro. The impact of BMPR2 signaling upon vascular cell functions and transcriptional activity will be investigated, as well as the potential mechanisms of effect. Cell physiology will be correlated with the impact of disrupting BMPR2 in vivo, using the endpoints of pulmonary vascular hemodynamic function, structure and development. These studies will help define the role of BMPR2 and BMP signaling in normal and pathologic vascular function and may provide an animal model of pulmonary hypertension. Completion of the research program and the acquisition of the required skills and experience will provide a solid foundation for the development of a career as a physician-scientist specializing in cardiac and pulmonary vascular biology. The principal investigator is transitioning from fellowship training to faculty in the Division of Cardiology at Massachusetts General Hospital and proposes to expand upon his scientific skills in molecular genetics, cell biology, and animal physiology to facilitate the transition to independence as an investigator skilled in integrating molecular and physiologic aspects of disease. The career development plan includes scientific and career mentorship from an advisory committee of accomplished scientists; participation in relevant seminars, courses, and national meetings; and the provision of protected research time. The proposal will take advantage of extensive local technical expertise and the highly collaborative environment present at Massachusetts General Hospital. Health Relevance: Bone morphogenetic proteins are used by cells to coordinate growth of new tissues and maintain existing tissues, and are especially important in developing and maintaining normal blood vessels. This study examines in mice how a receptor for bone morphogenetic proteins (BMPR2) coordinates the function of blood vessel cells, and how abnormal function of BMPR2 may lead to disorders of the circulation. (End of Abstract)