MECHANISMS REGULATING NUTRITIVE CEREBRAL BLOOD FLOW

对营养性血流的调节大脑是一个 提供底物以满足基本氧化的动态过程 底物的中枢神经系统，同时提供充血流动，以代谢 活跃地区。脑血流调节的基础是 大脑微循环的自动调节能力。开始 理解这一过程需要对细胞的基本定义， 毛细血管前小动脉感知的分子机制 环境条件并启动适当的信号转导 激活或抑制微血管和平滑肌收缩的事件 肌肉.定义旨在调节营养的稳态机制 脑血流量（CBF）在综合功能水平，以满足 生理需求超出了任何一个实验室的范围。大卫医生 哈德将指导该计划，并领导项目1。项目研究 1将侧重于分子，细胞和信号转导 在面对波动时介导营养性CBF的自动调节 动脉压我们最近测序了细胞色素P450（P450） 离体毛细血管前小动脉肌内的ω-羟化酶基因 细胞，其编码催化20-HETE形成的酶 花生四烯酸（AA）。抑制20-HETE形成消除了 正常的，几乎完美的，激光多普勒血流的自动调节， 大鼠顶叶皮质动脉压升高。 计划2 将由理查德·罗曼博士领导， 一氧化氮（NO）和P450之间产生20-HETE形成。在 营养性CBF的调节NO似乎直接与血红素结合 部分，并抑制P450酶活性。roman医生提供 令人信服的数据，假设cGMP独立的机制， NO的作用是抑制P450 4A ω-羟化酶活性， 阻断内源性20-HETE的产生，20-HETE是最有效的血管活性物质之一， 探员身份不明项目3将由Raymond Koehler博士领导 （约翰霍普金斯大学医学院），其中定义了 星形胶质细胞P450表氧化酶活性在功能性充血中的作用 个脑袋我们已经从星形胶质细胞中测序了P450 2C 11 cDNA， 一种产生扩张性环氧二十碳三烯酸的蛋白质。 谷氨酸诱导EET释放并调节2C 11基因表达。 博士克勒和他在约翰霍普金斯大学的合作者有必要的 专业知识来定义的作用的生理意义 星形胶质细胞衍生的Ehrs在抑制压力依赖性激活的 毛细血管前循环和介导功能性充血。大 范围、共同主题和应用多种最新技术 技术需要医疗机构之间的方案倡议， 威斯康星州学院和约翰霍普金斯大学在这份 应用程序.这是一个重新提交，并已大幅修改 沿着科学评论研究部分建议的路线。

Regulation of nutritive blood flow the brain is an extraordinarily dynamic process providing substrate to meet essential oxidative substrate to the CNS, while providing hyperemic flow to metabolically active areas. Fundamental to brain blood flow regulation is the autoregulatory capacity of the cerebral microcirculation. To begin to understand this process requires a basic definition of the cellular and molecular mechanisms through which pre-capillary arterioles sense environmental conditions and initiate appropriate signal transduction events to activate or inhibit contraction of microvascular and smooth muscle. Defining homeostatic mechanisms designed to regulate nutritive cerebral blood flow (CBF) at an integrated functional level to meet physiologic demand is beyond the scope of any one laboratory. Dr. David Harder will Direct this Program, and lead Project 1. Studies in Project 1 will focus on the molecular, cellular and signal transduction mediating autoregulation of nutritive CBF in the face of a fluctuation arterial pressure. We have recently sequenced a cytochrome P450 (P450) omegahydroxylase gene within isolated pre-capillary arteriolar muscle cells which codes for an enzyme catalyzing formation of 20-HETE from arachidonic acid (AA). Inhibition of 20-HETE formation abolishes the normal, nearly perfect, autoregulation of laser-Doppler blood flow to elevation of arterial pressure in the rat parietal cortex. Project 2 will be lead by Dr. Richard Roman, and will define the interactions between nitric oxide (NO) and P450 generated 20-HETE formation. In the regulation of nutritive CBF NO appears to bind directly to the heme moiety of, and inhibit P450 enzyme activity. Dr. roman provides compelling data for the hypothesis that the cGMP independent mechanisms of action of NO is to inhibit P450 4A omega-hydroxylase activity and block endogenous production of 20-HETE one of the most potent vasoactive agents yet identified. Project 3 will be lead by Dr. Raymond Koehler (Johns Hopkins University School of Medicine) which defines the role of astrocytic P450 epoxygenase activity in functional hyperemia in the brain. We have sequenced a P450 2C11 cDNA from astrocytes which does for a protein generating dilatory epoxyeicositrienoic acids (EETs). Glutamate induces release of EETs and regulates 2C11 gene expression. Dr. Koehler and his collaborators at Johns Hopkins have the necessary expertise to define the physiological significance of the role of astrocyte derived EETs in dampening pressure-dependent activation of the pre-capillary circulation and mediating functional hyperemia. The large scope, common theme and application of multiple state-of-the-art techniques necessitates the programmatic initiative between the Medical College of Wisconsin and Johns Hopkins University proposed in this application. This is a resubmission and has been substantially revised along the line suggested by the scientific review study sections.