Regional and cellular significance of brain renin angio

尽管经过30多年的研究，大脑中的肾素-血管紧张素系统（RAS）仍然无法解释。 我们缺乏对大脑RAS在细胞和区域水平上如何组织的理解，使得难以解决长期寻求的问题，即血管紧张素II（AngII）如何在大脑中产生，以及它发挥作用的确切机制。 一个主要原因是在实验上解剖大脑RAS的困难-在区域，细胞和整个生物体水平。 在上一个资助期间，我们已经开发了一系列遗传工具，用于在体内细胞和位点选择性地操纵小鼠大脑RAS。 此外，我们已经建立了最先进的技术，用于长期分析清醒小鼠的血压和容量稳态。 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解剖大脑RAS的区域，细胞（神经元与神经胶质细胞）和功能意义。专注于关键的心血管调节中心，包括穹窿下器官耦合网络参与加压素的释放和交感神经流出，我们将确定精确的机制，大脑血管紧张素II的生产和行动，在这些途径。我们也将开始进一步探索一个潜在的令人兴奋的新的中央血管紧张素II信号机制，涉及活性氧。 我们相信这些研究有可能澄清大脑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液体平衡的理解。

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.