The role of the BMP type II receptor in vascular function

这项研究旨在检测骨形态发生蛋白（BMP）信号在骨形成中的作用。 脉管系统该领域的先前工作已经证明了BMP信号对细胞功能的影响。 血管内皮细胞和平滑肌细胞，表明BMP信号是血管内皮细胞和平滑肌细胞的重要调节因子。 形成和重塑。BMP信号的主要受体BMP的功能丧失突变 II型受体（BMPR 2）与血管病变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信号传导的机制 改变血管组织的功能是不完全确定的。Cre-lox系统的使用和遗传学 修饰的小鼠已经允许在体内和体外对BMPR 2基因进行组织特异性破坏。的影响 将研究BMPR 2信号传导对血管细胞功能和转录活性的影响，以及BMPR 2信号传导对血管细胞功能和转录活性的影响。 潜在的影响机制。细胞生理学将与破坏BMPR 2在细胞中的影响相关。 在体，采用终点肺血管血流动力学功能，结构和发展。这些 研究将有助于确定BMPR 2和BMP信号在正常和病理血管功能中的作用， 可以提供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一个 职业生涯作为一个医生，科学家专门从事心脏和肺血管生物学。 主要研究者正在从研究员培训过渡到心脏病学部门的教员， 马萨诸塞州总医院，并建议扩大他在分子遗传学，细胞， 生物学和动物生理学，以促进过渡到独立作为一个调查员熟练， 整合疾病的分子和生理方面。职业发展计划包括科学 和职业指导;参加有关的 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 利用广泛的本地技术专长和高度协作的环境， 马萨诸塞州综合医院。 健康相关性：骨形态发生蛋白被细胞用来协调新组织的生长， 维持现有的组织，并且在发育和维持正常血管中特别重要。 这项研究在小鼠中检测了骨形态发生蛋白受体（BMPR 2）如何协调骨形成。 血管细胞的功能，以及BMPR 2的异常功能如何导致循环障碍。

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.