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

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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