Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension

描述(由申请人提供)： 项目主任/首席研究员(最后、第一、中间)：Grobe，Justin L.项目摘要新陈代谢和心血管疾病都对美国和世界各地成年人的健康构成了重大威胁。这两种类型的疾病至少存在于33%的人口中，这些疾病造成的经济、社会、心理和生产力负担估计超过5300亿美元。参与新陈代谢和心血管功能调节的一个激素系统是肾素-血管紧张素系统(RAS)。虽然RAS在体内的许多组织中都有发现，但西格蒙德实验室之前已经开发出一种转基因小鼠模型(SRA模型)，在该模型中，RAS的过度活动仅限于中枢神经系统。在这些小鼠中，RAS的脑特异性过度活动导致中度高血压和心脏重构，基础代谢率大幅增加，体重持续下降，肥胖症减少。目前的建议将评估大脑内诱导这些表型的血管紧张素能信号通路(在指导阶段)，然后检查调节这些表型的传出和外周机制(在建立独立的研究实验室时)。具体地说，在指导阶段，候选人将学习与显微注射传递病毒相关的技术，这些病毒可在选定的脑结构内诱导基因重组(病毒准备/使用、凝胶微注射、免疫组织学、小样本RNA制备、定量聚合酶链式反应)。此外，在指导阶段，候选人将继续他的专业发展(指导初级同事，进一步扩大智力和合作资源，以及独特的靠近一个主要领域特定科学期刊的编辑部)。总体而言，该项目将促进对候选人的持续技术、智力和专业培训，并帮助在学术研究机构建立独立的研究实验室。PHS 398/2590(11/07版)延续格式页面 公共卫生相关性： 项目主任/首席研究员(最后、第一、中间)：Grobe，Justin L.相关性肾素-血管紧张素系统(RAS)是一种激素系统，参与调节肾脏、心脏和血管的结构和功能、液体和钠的消耗行为、血压和代谢率。在目前的方案中，利用具有脑特异性RAS过度活性的转基因小鼠来评估大脑RAS调节新陈代谢和水矿物平衡的机制。PHS 398/2590(11/07版)延续格式页面

DESCRIPTION (provided by applicant): Program Director/Principal Investigator (Last, First, Middle): GROBE, JUSTIN L. Project Summary Metabolic and cardiovascular disorders both pose significant threats to the health of the adult population of the United States and world-wide. Both types of disorders are present in at least 33% of the population, and the economic, social, psychological, and productivity burdens which result from these disorders are estimated to be in excess of $530 billion. One hormone system involved in the regulation of both metabolism and cardiovascular function is the Renin- Angiotensin System (RAS). While the RAS is found in many tissues throughout the body, the Sigmund laboratory has previously developed a transgenic mouse model (the sRA model) in which overactivity of the RAS is limited to the central nervous system. Brain-specific overactivity of the RAS in these mice results in moderate hypertension and cardiac remodeling, a large increase in basal metabolic rate, sustained depression of body mass, and decreased adiposity. The current proposal will evaluate the angiotensinergic signaling pathways within the brain which induce these phenotypes (during the mentored phase), and then examine the efferent, peripheral mechanisms which mediate these phenotypes (upon the establishment of an independent research laboratory). Specifically, during the mentored phase, the candidate will learn techniques related to the microinjection delivery of viruses which induce gene recombination within select brain structures (viral preparation/use, electrophoretic microinjection, immunohistology, small-sample RNA preparation, quantitative PCR). Additionally, during the mentored phase, the candidate will continue his professional development (mentoring of junior colleagues, further expansion of intellectual and collaborative resources, and the unique proximity to the editorial office of a major area-specific scientific journal). Collectively, this project will facilitate continued technical, intellectual, and professional training for the candidate, and assist in the establishment of an independent research laboratory at an academic research institution. PHS 398/2590 (Rev. 11/07) Continuation Format Page PUBLIC HEALTH RELEVANCE: Program Director/Principal Investigator (Last, First, Middle): GROBE, JUSTIN L. Relevance The Renin-Angiotensin System (RAS) is a hormone system involved in the regulation of renal, cardiac, and vascular structure and function, fluid and sodium consummatory behavior, blood pressure, and metabolic rate. In the current proposal, transgenic mice with brain-specific overactivity of the RAS are utilized to evaluate the mechanisms by which the brain's RAS regulates metabolism and hydromineral balance. PHS 398/2590 (Rev. 11/07) Continuation Format Page