Modification of Vascular Signaling in the Brain by ROS

ROS 改变大脑血管信号传导

• 批准号: 8009430
• 负责人: David Rae Harder
• 金额: $ 41.01万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009430
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adenosine; Area; Astrocytes; Behavior; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Calcium-Activated Potassium Channel; Caliber; Cardiac Output; Cell membrane; Cells; Cerebrovascular Circulation; Cerebrum; Clinical Trials; Code; Color; Confocal Microscopy; Data; Development; Diffuse; Dose; Elements; Endothelial Cells; Endothelium; Event; Exhibits; Fluo-3; Fluorescein; Fluorescence; Foot Process; Free Radicals; Future; GTP-Binding Proteins; Generations; Glial Fibrillary Acidic Protein; Glutamates; Grouping; Health; Homeostasis; Hydrogen Peroxide; Image; Individual; Label; Laboratories; Link; Location; Maintenance; Measurable; Measures; Mediating; Mediator of activation protein; Membrane; Metabolic; Microcirculation; Modeling; Modification; Molecular Mechanisms of Action; Muscle; Muscle Cells; Neurons; Organ; Oxygen; PLC gamma1; PTEN gene; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase; Phospholipase C; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Potassium Channel; Production; Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Regulation; Relative (related person); Resistance; Rest; Rhodamine; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Staining method; Stains; Structure; Testing; Time; Variant; Vascular Endothelium; Vascular Smooth Muscle; Work; arteriole; capillary; cerebral artery; in vivo; indexing; mathematical algorithm; neurovascular unit; novel; pressure; relating to nervous system; response; uptake

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.

描述（由申请人提供）：关于活性氧（ROS）和血流控制的大部分已知知识都是现象学的，对细胞和分子作用机制的了解较少。这个提议的目的是定义一些细胞和离子机制，通过这些机制，O2。-和H2O2调节脑血流（CBF）的肌源性自动调节。H2O2降低了孤立的受压脑小动脉在跨壁压力升高时的自调节程度（自调节指数，AI），以及在体内平均动脉压升高时的自调节程度（AI）。H2O2减少平滑肌激活的作用似乎涉及通过磷脂酶C γ -1和相关磷酸肌醇3激酶和磷酸酶启动的信号级联的调节。H2O2的部分信号级联涉及激活由PKC调节的Ca2+激活的K+通道。这些数据证明了O2的细胞/离子机制。-和H2O2对脑动脉肌肉的影响和自动调节是通过PIP2的裂解和由此产生的IP3和DAG的形成。我们发现，从代谢活跃的神经元和星形胶质细胞释放的腺苷启动脑动脉肌细胞中ROS的形成。这样的数据链接神经元代谢活动调节压力依赖性肌张力-因此，定义O2的作用。-和H2O2对静息条件下脑血流的自动调节和神经代谢活动增加的反应。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。虽然这些都是未来的计划，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、肌源性和代谢反应及其机制。以前的模型已经开发，只探索了自动调节，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；Beard已同意担任我们的顾问，并使用该项目获得的数据指导未来脑血流调节模型的基础和临床研究。与公共卫生相关：流向大脑的血液的调节方式不同于流向其他器官的血液。大脑是一个刚性封闭的空间，因此，血流必须自动调节，以使动脉压力的变化不会引起大脑压力的变化。这种自我调节是由分子控制的，当神经元需要更多的氧气时，分子会感觉到血液的需要。此外，脑血管表现出自己的控制称为肌张力。这种肌原性张力是该应用的主要主题。我们将确定肌原性张力是如何发生的，以及在正常和异常情况下是如何调节的，以确保有足够的血液流向神经元，这样大脑才能正常工作。