Regional and cellular significance of brain renin angio

脑肾素血管的区域和细胞意义

• 批准号: 6704841
• 负责人: Robin L Davisson
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-21 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704841
• 关键词: angiotensin II; angiotensin receptor; blood pressure; brain mapping; brain regulatory center; cerebrovascular system; free radical oxygen; genetically modified animals; glia; hormone regulation /control mechanism; laboratory mouse; neurons; renin angiotensin system; telencephalon

Despite more than 30 years of study, the brain renin-angiotensin system (RAS) continues to defy explanation. Our lack of understanding of how the brain RAS is organized at the cellular and regional levels has made it difficult to resolve long-sought questions of how angiotensin II (AngII) is produced in the brain, and the precise mechanisms by which it exerts its actions. A major reason for this is the difficulty in experimentally dissecting the brain RAS- at the regional, cellular and whole organism levels. During the last funding period we have developed an array of genetic tools to cell- and site-selectively manipulate the murine brain RAS in vivo. Furthermore, we have established state-of-the-art technology for long-term analysis of blood pressure and volume homeostasis in conscious mice. Harnessing the power of a combination of these new tools, we will dissect the regional, cellular (neurons vs. glia) and functional significance of the brain RAS in the context of both physiological and pathophysiological states. Focusing on critical cardiovascular regulatory centers, including subfornical organ coupled networks involved in vasopressin release and sympathetic outflow, we will determine precise mechanisms of brain AngII production and action in these pathways. We will also begin to further explore a potentially exciting new central AngII signaling mechanism involving reactive oxygen species. We believe these studies have the potential to clarify the basic biology of the brain RAS, and impact our understanding of how this system regulates cardiovascular and fluid balance in normal and disease states.

尽管进行了30多年的研究，但大脑肾素 - 血管紧张素系统（RAS）仍在继续反对解释。 我们对在细胞和区域层面上如何组织脑RA的理解缺乏理解，因此很难解决长期以来的问题，即在大脑中如何产生血管紧张素II（Angii），以及其发挥作用的确切机制。 造成这种情况的主要原因是在区域，细胞和整个生物体水平上实验剖析脑ras的困难。 在最后的资金期间，我们开发了一系列遗传工具，用于在体内操纵鼠脑Ras。 此外，我们已经建立了最先进的技术，用于长期分析有意识的小鼠血压和体积体内稳态。 利用这些新工具的组合的力量，我们将在生理和病理生理状态的背景下剖析脑RA的区域性，细胞（神经元与神经胶质）和功能意义。专注于关键的心血管调节中心，包括参与加压素释放和交感神经流出的次型器官耦合网络，我们将确定在这些途径中脑Angii生产和作用的精确机制。我们还将开始进一步探索涉及活性氧的潜在令人兴奋的新中央ANGII信号传导机制。 我们认为，这些研究有可能阐明脑RA的基本生物学，并影响我们对该系统如何调节正常和疾病状态中心血管和液体平衡的理解。