BMPR2, the type 2 Bone Morphogenetic Protein (BMP) Receptor, plays essential roles in mammalian development and homeostasis. The adult role played by BMPR2 signaling emerged as a result of the identification of mutations in the BMPR2 gene in familial forms of pulmonary arterial hypertension in humans. While BMP signaling is implicated in blood vessel development, the specific molecular connections between receptor activation and intracellular signaling and gene expression are poorly understood. To better understand how loss of BMPR2 causes abnormal BMP signaling, defective blood vessel growth in living animals, we have used zebrafish (ZF) to explore BMP signaling in vascular development. Loss of BMPR2 in ZF causes (a) abnormal blood vessel development and growth, (b) increased Smad-1/5/8 and ERK1/2 activity, and (c) decreased expression of wntl 1 and b-catenin1. To provide new insights into the role of BMP signaling in vascular development, we will (Aim 1) characterize blood vessel abnormalities caused by loss of BMPR2;
(Aim 2) assess receptor defects which cause abnormal signaling, and (Aim 3) explore key downstream signaling changes in ERK and wnt caused by loss of BMPR2. Acquisition of the skills and experience necessary to complete the research plan will provide a solid foundation for the candidate to develop a career as an independent physician-scientist specializing in cardiovascular developmental biology. To facilitate the emergence of the PI as an independent investigator, a career development plan is proposed which 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 application capitalizes on extensive expertise, exceptional resources, and a highly collaborative environment present both at the Massachusetts General Hospital and Harvard Medical School. Health Relevance: BMPs are used generally by cells and organisms to coordinate growth and homeostasis, and specifically have important roles in blood vessel growth and development. Loss of BMPR2 disrupts normal development and causes abnormal vascular homeostasis. In humans, mutations in BMPR2 cause pulmonary hypertension. This study uses ZF to understand how defective BMPR2 causes disorders of blood vessel growth and function, to better understand its role in development and disease.
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