Modification of Vascular Signaling in the Brain by ROS

ROS 改变大脑血管信号传导

• 批准号: 7582973
• 负责人: David Rae Harder
• 金额: $ 40.97万
• 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/7582973
• 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; Face; Fluo-3; Fluorescein; Fluoresceins; Fluorescence; Foot Process; Free Radicals; Future; GTP-Binding Proteins; Generations; Glial Fibrillary Acidic Protein; Glutamates; Grouping; 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; Rhodamines; 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; public health relevance; 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）和血流的控制的许多知识是现象学的，对细胞和分子作用机制的了解较少。该建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调节大脑血流（CBF）的肌源性自动调节。 H2O2降低了自动调节的程度（自动调节指数，AI），响应于分离的加压脑小动脉的透射压力增加，并在体内增加平均动脉压时降低AI。 H2O2减少平滑肌激活的作用似乎涉及通过磷脂酶C Gamma-1引发的信号级联反应的调节，以及相关的磷酸辅醇3激酶和磷酸酶。 H2O2信号级联的一部分涉及由PKC调节的Ca2+激活的K+通道的激活。这些数据表明，O2.-和H2O2在脑动脉肌肉和自动调节上的细胞/离子机制是通过PIP2的裂解以及IP3和DAG的导致形成的。我们发现，从代谢活性神经元和星形胶质细胞释放的腺苷会引发大脑动脉肌肉细胞中ROS的形成。这样的数据将神经元代谢活性调节压力依赖性肌源性张力 - 从而定义了O2.和H2O2对静止条件下CBF自动调节的作用，并响应增加的神经代谢活性。我们希望开发一种数学算法来刺激大脑中的局部血流。尽管这些是未来的计划，但它们的可能性是，该模型将包括可测量的参数，即被动，剪切依赖性，肌原性和代谢反应及其机制。先前的模型已经开发，并且仅探索自动调节，并且无法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，并使用该项目中获得的数据，以指导未来的基本和临床研究对脑血流调节模型。公共卫生相关性：向大脑的血液流动与其他器官的调节不同。大脑在刚性的封闭空间中，因此必须对血流进行自动调节，以使动脉压的变化不会导致大脑压力的变化。这种自动调节受到分子的控制，因为神经元需要更多的氧气，这种分子感知血液的需求。此外，大脑血管表现出自己的控制称为肌吻合。这种肌源性语调是该应用程序的主要主题。我们将确定肌源性的发生方式，以及如何在正常和异常条件下调节肌定语，以确保有足够的血液流向神经元，以便大脑可以正常工作。