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.
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