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Modification of Vascular Signaling in the Brain by ROS

ROS 改变大脑血管信号传导

基本信息

批准号：
8399039
负责人：
David Rae Harder
金额：
$ 39.04万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8399039
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 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

项目摘要

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.

关于活性氧 (ROS) 和血液控制的大部分知识流动是现象学的，对细胞和分子的了解较少行动机制。该提案的目的是定义一些蜂窝和 O2.- 和 H2O2 调节肌源性自动调节的离子机制脑血流量（CBF）。 H2O2 降低自动调节程度（autoregulatory 指数，AI）响应增加的跨壁压力在两个隔离加压脑小动脉以及在增加体内平均动脉压时降低 AI。 H2O2 减少平滑肌激活的作用似乎涉及调节通过磷脂酶 C gamma-1 和相关磷酸肌醇启动的信号级联 3 激酶和磷酸酶。 H2O2 信号级联的一部分涉及激活 Ca2+ 激活受 PKC 调节的 K+ 通道。这些数据表明 O2.- 和 H2O2 对脑动脉肌肉的细胞/离子机制自我调节是通过 PIP2 的裂解以及由此形成的 IP3 和 DAG 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启动脑动脉肌细胞中ROS的形成。这些数据将神经元代谢联系起来调节压力依赖性肌原性张力的活动 - 从而定义 O2.- 和 H2O2 对静息条件下 CBF 的自动调节和响应神经代谢活动增加。我们希望开发一种数学算法刺激大脑局部血流。虽然这些是未来的计划，但它们有可能该模型将包括可测量的参数，即被动参数、剪切相关参数、肌源性和代谢反应及其机制。以前的型号已经已经发展起来，只探索了自动调节，还无法区分上述参数的相对浓度。我们希望丹尼尔博士；胡须已同意担任我们的顾问并使用在该项目中获得的数据来指导未来脑血流调节模型的基础和临床研究。