Modification of Vascular Signaling in the Brain by ROS

关于活性氧簇(ROS)和血液控制的许多已知知识 流是现象学的，关于细胞和分子的了解较少 行动机制。这项提案的目的是定义一些蜂窝和 O_2~(2-)和H_2O_2调节肌源性自身调节的离子机制 脑血流量(CBF)。过氧化氢降低了自动调节的程度(自动调节 指数，AI)对两个隔离加压的跨室壁压力增加的反应 在活体内，通过增加平均动脉压，还可以减少大脑小动脉，并降低AI。 H_2O_2减少平滑肌激活的作用似乎涉及对 通过磷脂酶C-1和相关的磷脂酰肌醇启动的信号级联反应 3激酶和磷酸酶。过氧化氢引起的信号级联反应的一部分涉及激活 CA2激活受PKC调控的K通道。这些数据表明， O_2~-和H_2O_2对脑动脉肌细胞/离子机制的影响 自身调节是通过裂解PIP2和形成IP3和DAG来实现的。我们有 发现从代谢活跃的神经元和星形胶质细胞释放的腺苷 脑动脉肌细胞内ROS的形成。这样的数据将神经元代谢联系起来 调节压力依赖性肌源性张力的活动--从而定义 O_2~-和H_2O_2在静息状态下对脑血流量的自动调节作用 神经代谢活动增强。我们希望开发一种数学算法来 刺激大脑的局部血液流动。虽然这些都是未来的计划，但它们可能在 该模型将包括可测量的参数，即被动的、剪切相关的、 肌源性和代谢反应及其机制。之前的型号一直是 开发并只探索了自动调节，还不能区分 上述参数的相对浓度。我们希望丹尼尔博士；比尔德博士 已同意担任我们的顾问，并使用在此项目中获得的数据来指导未来 脑血流调节模型的基础与临床研究。

Much of what is known about reactive oxygen species (ROS) and the control of blood flow is phenomenological with less understood regarding cellular and molecular mechanisms of action. The purpose of this proposal is to define some of the cellular and ionic mechanisms through which O2.- and H2O2 modulate myogenic autoregulation of cerebral blood flow (CBF). H2O2 reduces the degree of autoregulation (autoregulatory index, AI) in response to increasing transmural pressure in both isolated pressurized cerebral arterioles as well as reducing AI upon increasing mean arterial pressure in vivo. The action of H2O2 to reduce smooth muscle activation appears to involve modulation of the signaling cascade initiated via phospholipase C gamma-1, and related phosphoinositol 3 kinase and phosphatases. Part of the signaling cascade by H2O2 involves activation of Ca2+ activated K+ channels regulated by PKC. These data demonstrate that the cellular/ionic mechanisms of O2.- and H2O2 on cerebral arterial muscle and autoregulation is via cleavage of PIP2 and resultant formation of IP3 and DAG. We have found that adenosine, released from metabolically active neurons and astrocytes initiates formation of ROS in cerebral arterial muscle cells. Such data links neuronal metabolic activity modulating pressure-dependent myogenic tone - thereby, defining the actions of O2.- and H2O2 on autoregulation of CBF under resting conditions and in response to increased neural metabolic activity. We hope to develop a mathematical algorithm to stimulate local blood flow in the brain. While these are future plans they are possible in that the model will include measurable parameters i.e. passive, shear-dependent, myogenic and metabolic responses and their mechanisms. Previous models have been developed and have only explored autoregulation and have not been able to distinguish the relative concentrations of the aforementioned parameters. We hope Dr. Daniel; Beard has agreed to act as our consultant and use data obtained in this project to guide future basic and clinical investigations into models of cerebral blood flow regulation.