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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

基本信息

批准号：
8231353
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231353
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

项目摘要

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）： BMPR 2是2型骨形态发生蛋白（BMP）受体，在哺乳动物的发育和体内平衡中起着重要作用。BMPR 2信号传导所起的成人作用是由于在人类家族性肺动脉高压中BMPR 2基因突变的鉴定而出现的。虽然BMP信号传导与血管发育有关，但受体活化与细胞内信号传导和基因表达之间的特定分子联系知之甚少。为了更好地理解BMPR 2的缺失如何导致BMP信号异常，在活体动物中有缺陷的血管生长，我们使用斑马鱼（ZF）来探索血管发育中的BMP信号。ZF中BMPR 2的缺失导致（a）异常的血管发育和生长，（B）增加的Smad-1/5/8和ERK 1/2活性，和（c）减少的wntl 1和b-连环蛋白1的表达。为了对BMP信号传导在血管发育中的作用提供新的见解，我们将（目的1）表征由BMPR 2缺失引起的血管异常;（目的2）评估引起异常信号传导的受体缺陷，以及（目的3）探索由BMPR 2缺失引起的ERK和wnt的关键下游信号传导变化。获得完成研究计划所需的技能和经验将为候选人发展作为心血管发育生物学专业的独立医生科学家的职业生涯奠定坚实的基础。为了促进PI作为独立研究者的出现，提出了一个职业发展计划，其中包括来自有成就的科学家咨询委员会的科学和职业指导;参加相关研讨会，课程和国家会议;并提供受保护的研究时间。该应用程序利用了马萨诸塞州总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。健康相关性：BMP通常被细胞和生物体用于协调生长和体内平衡，特别是在血管生长和发育中具有重要作用。BMPR 2的缺失破坏正常发育并导致异常的血管稳态。在人类中，BMPR 2的突变导致肺动脉高压。该研究使用ZF来了解缺陷BMPR 2如何导致血管生长和功能障碍，以更好地了解其在发育和疾病中的作用。 (End摘要）