Modification of Vascular Signaling in the Brain by ROS

ROS 改变大脑血管信号传导

• 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
• 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

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.

许多关于活性氧（ROS）和血液控制的知识 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 通过离子机制，和H2 O2调节肌源性自身调节 脑血流量（CBF）。H2 O2降低了自动调节的程度（自动调节 指数，AI）对两种隔离加压中跨壁压增加的反应 脑小动脉以及在体内增加平均动脉压后降低AI。 H2 O2减少平滑肌激活的作用似乎涉及调节 通过磷脂酶C γ-1和相关的磷酸肌醇启动的信号级联 3激酶和磷酸酶。H2 O2的部分信号级联涉及激活 Ca ~（2+）激活的K ~+通道受PKC调节。这些数据表明 O2的细胞/离子机制。和H2 O2对脑动脉肌肉的影响， 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。我们有 发现腺苷，从代谢活跃的神经元和星形胶质细胞释放启动， 脑动脉肌细胞内ROS的形成。此类数据将神经元代谢联系起来 活性调节压力依赖性肌源性张力-从而，定义了 氧气和H_2O_2对静息状态下CBF的自动调节以及对 增加神经代谢活动。我们希望开发一种数学算法， 刺激大脑局部的血液流动虽然这些都是未来的计划， 该模型将包括可测量的参数，即被动，剪切相关， 生肌和代谢反应及其机制。以前的模型已经被 发展和只探索自动调节，并没有能够区分 上述参数的相对浓度。我们希望丹尼尔医生;比尔德 已同意担任我们的顾问，并利用在这个项目中获得的数据来指导未来的工作。 脑血流调节模型的基础和临床研究。