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Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension

调节大脑 RAS 活性的新机制：在神经源性高血压中的作用

基本信息

批准号：
10213809
负责人：
Curt Daniel Sigmund
金额：
$ 47.7万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213809
关键词：
Address Alleles Angiotensin II Angiotensinogen Blood Blood Pressure Brain Budgets CRISPR/Cas technology Cardiovascular system Cell Line Cell Nucleus Cells DOCA Data Disinhibition Energy Metabolism Exhibits Exons Experimental Water Deprivation Exposure to Future Generations Genes Genetic Genetic Transcription High Fat Diet Homeostasis Hypertension Hypothalamic structure Impairment In Vitro Inactive Renin Intake Kidney Light Liquid substance Mediating Messenger RNA Metabolic Methods Modeling Molecular Mus Nerve Neuroglia Neurons Pathologic Peptide Signal Sequences Physiological Play Prevention Production Prosencephalon Protein Isoforms Regulation Renin Renin-Angiotensin System Reporter Role Seminal Signal Transduction Site Sodium Chloride Stimulus Structure of nucleus infundibularis hypothalami Subfornical Organ Sympathetic Nervous System System Testing Upstream Enhancer dietary extracellular genetic manipulation genome editing inhibitor/antagonist innovation mouse model neuroblastoma cell neurogenic hypertension novel paraventricular nucleus preservation promoter receptor response stressor synergism

项目摘要

Summary/Abstract The brain renin-angiotensin system (RAS) plays a crucial role in regulating cardiovascular and metabolic function. Nuclei-specific synthesis and action of angiotensin-II (ANG) in the brain affords mechanisms for the independent regulation of fluid intake and sympathetic nerve activity (SNA) controlling blood pressure (BP) and metabolic responses. That angiotensinogen (AGT), the substrate for renin and precursor to ANG is constitutively released from glial cells throughout the brain, and from neurons in nuclei controlling cardiovascular and metabolic function, implores the central question of how ANG production in the brain is regulated? We identified an unexpected and novel mechanism regulating expression of renin in the brain which may address this. However, the initiating signals and mechanisms involved remains unknown. This project will examine the innovative concepts and hypotheses that: 1) there is coordinate regulation of renin mRNA isoforms which controls RAS activity in the brain, and 2) impairment of this novel control mechanism causes neurogenic hypertension and increases sensitivity of exposure to hypertension-causing stimuli. We will examine this original concept in the following two specific aims: 1) test the hypothesis that coordinated expression of Ren-b and Ren-a in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate nucleus (ARC) mediates local ANG production and action which alters SNA controlling cardiovascular and metabolic function, and 2) test the hypothesis that disinhibition of Ren-a expression with concomitant inhibition of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive response (HTR) to mild humoral (e.g. ANG) and dietary (e.g. high fat diet) stressors. The studies will advance the concepts that a) Ren-b expression is an endogenous inhibitor of Ren-a expression limiting ANG production in the presence of excess extracellular AGT, and b) under conditions which threaten homeostasis (e.g. water deprivation) or in response to pathological stimuli (e.g. DOCA-salt or high fat diet), previously dormant Ren-a expression is disinhibited leading to site-specific prorenin activation, ANG generation and ANG action. Importantly, we hypothesize that impairment of this regulatory circuit causes neurogenic hypertension. The project has natural synergy as other projects that will similarly examine blood pressure and metabolic signaling in forebrain and hypothalamic nuclei. Moreover, this project will be informed by the data collected by the other projects and will synergize by exploring RAS-dependent and renin-dependent mechanisms in those systems.

摘要/文摘