Modification of Vascular Signaling in the Brain by ROS

描述（由申请人提供）：关于活性氧（ROS）和血流控制的许多已知内容是现象学的，对细胞和分子作用机制的了解较少。本提案的目的是定义一些细胞和离子机制，通过这些机制，O2。和H2 O2调节脑血流量（CBF）的肌源性自动调节。H2 O2降低了自动调节的程度（自动调节指数，AI）在两个孤立的加压脑小动脉的跨壁压增加，以及减少AI后，增加平均动脉压在体内。H2 O2减少平滑肌激活的作用似乎涉及通过磷脂酶C γ-1和相关的磷酸肌醇3激酶和磷酸酶启动的信号级联的调节。H_2O_2信号级联反应的一部分涉及PKC调节的Ca ~（2+）激活的K ~+通道的激活。这些数据表明，细胞/离子机制的O2。和H_2O_2对脑动脉肌的作用及其自身调节是通过PIP_2的裂解和由此产生的IP_3和DAG的形成来实现的。我们已经发现，腺苷，从代谢活跃的神经元和星形胶质细胞释放启动形成的活性氧在脑动脉肌细胞。这些数据链接神经元代谢活动调节压力依赖性肌张力-从而定义O2的作用。和H2 O2对静息条件下CBF的自动调节和对增加的神经代谢活动的响应。我们希望开发一种数学算法来刺激大脑中的局部血液流动。虽然这些是未来的计划，但它们是可能的，因为模型将包括可测量的参数，即被动、剪切依赖、生肌和代谢反应及其机制。以前的模型已经开发出来，只探讨了自动调节，并没有能够区分上述参数的相对浓度。我们希望丹尼尔博士;比尔德已同意担任我们的顾问，并使用该项目中获得的数据来指导未来对脑血流调节模型的基础和临床研究。公共卫生相关性：血液流向大脑的调节方式与其他器官不同。大脑处于一个刚性的封闭空间中，因此，血流必须自动调节，以便动脉压的变化不会引起大脑中压力的变化。这种自动调节是由感觉到神经元需要更多氧气时对血液的需要的分子控制的。此外，脑血管表现出其自身的控制，称为肌源性张力。这种肌原性张力是本申请的主要主题。我们将确定肌源性张力如何发生，以及在正常和异常条件下如何调节，以确保有足够的血液流向神经元，使大脑能够正常工作。

DESCRIPTION (provided by applicant): 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 are 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. PUBLIC HEALTH RELEVANCE: Blood flow to the brain is regulated differently than that of other organs. The brain is in a rigid closed space, therefore, blood flow must be autoregulated so that a change in arterial pressure does not cause a change in pressure in the brain. This autoregulation is controlled by molecules which sense the need for blood as neurons need more oxygen. In addition, the cerebral vessels exhibit their own control termed myogenic tone. This myogenic tone is a major topic of this application. We will determine how myogenic tone occurs and how it is regulated under normal and abnormal conditions to make sure there is enough blood flow to neurons so the brain can work properly.