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：
8206555
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
项目类别：
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/8206555
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）和血液的控制已知的大部分流量是现象学的，关于细胞和分子的了解较少作用机理。该提议的目的是定义一些细胞和 O2.-和H2O2通过的离子机制调节了肌源性自动调节脑血流（CBF）。 H2O2降低了自动调节的程度（自动调节性索引，ai）响应于两个分离的加压中的透壁压力增加脑动脉以及体内平均动脉压的增加后，还会减少AI。 H2O2减少平滑肌激活的作用似乎涉及调制通过磷脂酶Cγ-1和相关的磷酸肌醇发起的信号传导级联 3个激酶和磷酸酶。 H2O2信号级联的一部分涉及激活由PKC调节的Ca2+激活的K+通道。这些数据表明 O2.-和H2O2的细胞/离子机制在脑动脉肌肉上自动调节是通过PIP2的切割和IP3和DAG的结果形成。我们有发现从代谢活性神经元和星形胶质细胞启动的腺苷释放大脑动脉肌肉细胞中ROS的形成。此类数据链接神经元代谢活动调节压力依赖性的肌源音 - 从而定义了 O2.-和H2O2在静止条件下对CBF自动调节并响应神经代谢活性增加。我们希望将数学算法开发为刺激大脑中的局部血流。虽然这些是未来的计划，但它们是可能的该模型将包括可测量的参数，即被动，剪切依赖性，肌原和代谢反应及其机制。以前的型号已经开发并仅探索自动调节，无法区分上述参数的相对浓度。我们希望丹尼尔博士；胡须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本和临床研究。