The role of BMPR2 in blood vesel development and patterning in vivo

BMPR2 在体内血管发育和模式形成中的作用

• 批准号: 8037012
• 负责人: JORDAN T SHIN
• 金额: $ 13.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037012
• 关键词: Adult; Advisory Committees; Animal Model; Animals; Arteriovenous malformation; Attenuated; BMPR2 gene; Biology; Blood; Blood Circulation; Blood Vessels; Bone Morphogenetic Proteins; Cardiovascular system; Cell Surface Receptors; Cell surface; Cells; Cessation of life; DNA; Data; Defect; Development; Development Plans; Developmental Biology; Disease; Down-Regulation; Environment; Foundations; Gene Expression; General Hospitals; Genetic Transcription; Growth; Growth and Development function; Health; Homeostasis; Human; In Vitro; Injection of therapeutic agent; Investigation; Jordan; Knowledge; Life; Ligands; Link; MAPK3 gene; Massachusetts; Mediating; Mentorship; Messenger RNA; Molecular; Molecular Genetics; Mus; Mutation; Optics; Organism; Pathway Analysis; Pathway interactions; Pattern; Phenocopy; Physicians; Play; Pulmonary Hypertension; Receptor Activation; Research; Research Personnel; Resources; Role; Scientist; Signal Transduction; Solid; System; Telangiectasis; Testing; Time; Transgenic Organisms; Vascular Diseases; Zebrafish; abstracting; angiogenesis; base; bone morphogenetic protein 2; bone morphogenetic protein receptors; career; career development; cell behavior; design; experience; human disease; in vivo; insight; malformation; medical schools; meetings; novel; programs; pulmonary arterial hypertension; receptor; research study; skill acquisition; tool; translational study; vasculogenesis; zebrafish development

DESCRIPTION (provided by applicant): 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. (End of Abstract)

描述(由申请人提供)： BMPR2是第二型骨形态发生蛋白(BMP)受体，在哺乳动物发育和动态平衡中发挥重要作用。BMPR2信号在成人中所起的作用是在人类家族性肺动脉高压中发现BMPR2基因突变的结果。虽然BMP信号与血管发育有关，但受体激活与细胞内信号和基因表达之间的特定分子联系却知之甚少。为了更好地了解BMPR2的缺失如何导致BMP信号异常，导致活动物血管生长缺陷，我们使用斑马鱼(ZF)来探索BMP信号在血管发育中的作用。ZF中BMPR2的缺失导致(A)血管发育和生长异常，(B)Smad-1/5/8和ERK1/2活性增加，(C)wntl 1和b-catenin 1表达减少。为了对BMP信号在血管发育中的作用提供新的见解，我们将(目标1)表征由BMPR2丢失引起的血管异常；(目标2)评估导致异常信号的受体缺陷，以及(目标3)探索由BMPR2丢失导致的ERK和WNT的关键下游信号变化。获得完成研究计划所需的技能和经验将为候选人发展心血管发育生物学专业的独立医生兼科学家的职业生涯奠定坚实的基础。为了促进独立调查员的出现，提出了一项职业发展计划，其中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。该应用程序利用了马萨诸塞州综合医院和哈佛医学院的广泛专业知识、特殊资源和高度协作的环境。与健康相关：BMP通常被细胞和生物体用来协调生长和动态平衡，特别是在血管的生长和发育中具有重要的作用。BMPR2的缺失扰乱了正常的发育，并导致了血管内稳态的异常。在人类中，BMPR2的突变会导致肺动脉高压。本研究使用ZF来了解BMPR2缺陷是如何导致血管生长和功能障碍的，以更好地了解它在发育和疾病中的作用。 (摘要结束)