The role of the BMP type II receptor in vascular function

这项拟议的研究考察了骨形态发生蛋白(BMP)信号在脑内的作用。 脉管系统。该领域以前的工作已经证明BMP信号对BMP功能的影响 血管内皮细胞和平滑肌细胞，提示BMP信号是血管的重要调节因子 更新换代和重塑。BMP信号的主要受体BMP功能丧失突变 II型受体(BMPR2)与血管病理性疾病--原发性肺动脉高压有关。 进一步支持在血管功能中的重要作用。然而，BMP信号传递的机制 修饰血管组织的功能还没有完全定义。Cre-lox系统的使用和遗传 经过改良的小鼠可以在体内和体外对BMPR2基因进行组织特异性破坏。网络的影响 将研究BMPR2信号对血管细胞功能和转录活性的影响，以及 潜在的作用机制。细胞生理学将与干扰BMPR2的影响相关 活体，利用肺血管血流动力学终点的功能、结构和发育。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和 可提供一种肺动脉高压的动物模型。完成研究计划和 获得所需的技能和经验将为发展 作为一名内科科学家，专门研究心脏和肺血管生物学。 首席研究员正在从研究员培训过渡到心脏病部门的教员， 并计划扩展他在分子遗传学、细胞学方面的科学技能 生物学和动物生理学，以促进向独立的转变，成为一名熟练于 整合疾病的分子和生理方面。职业发展规划包括科学的 和由杰出科学家组成的咨询委员会提供的职业指导；参与相关的 研讨会、课程和国家会议；以及提供受保护的研究时间。这项提议将 充分利用当地广泛的技术专长和目前高度协作的环境 麻省总医院。 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 维持现有的组织，对发展和维持正常的血管尤为重要。 这项研究考察了骨形态发生蛋白受体(BMPR2)是如何在小鼠体内协调 血管细胞的功能，以及BMPR2的功能异常如何导致循环障碍。

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, urther 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.