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.

尽管经过 30 多年的研究，大脑肾素-血管紧张素系统 (RAS) 仍然无法得到解释。 我们对大脑 RAS 在细胞和区域水平上如何组织缺乏了解，这使得我们很难解决长期以来所寻求的问题：血管紧张素 II (AngII) 在大脑中是如何产生的，以及它发挥作用的精确机制。 造成这种情况的一个主要原因是在区域、细胞和整个有机体水平上通过实验解剖大脑 RAS 存在困难。 在上一个资助期间，我们开发了一系列遗传工具，可以在体内对小鼠大脑 RAS 进行细胞和位点选择性操纵。 此外，我们还建立了最先进的技术，用于对清醒小鼠的血压和容量稳态进行长期分析。 利用这些新工具组合的力量，我们将在生理和病理生理状态的背景下剖析大脑 RAS 的区域、细胞（神经元与神经胶质）和功能意义。重点关注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穹窿下器官耦合网络，我们将确定大脑 AngII 产生和在这些途径中作用的精确机制。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枢 AngII 信号传导机制。 我们相信这些研究有可能阐明大脑 RAS 的基本生物学，并影响我们对该系统如何在正常和疾病状态下调节心血管和体液平衡的理解。