Regulation of Cerebral Blood Flow by Acid-Sensing Ion Channels (ASICs)

通过酸敏感离子通道 (ASIC) 调节脑血流量

• 批准号: 8486487
• 负责人: Frank M Faraci
• 金额: $ 35.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486487
• 关键词: ASIC channel; Acidosis; Acids; Affect; Aging; Amygdaloid structure; Attenuated; Behavior; Bicarbonates; Blood Vessels; Blood flow; Brain; Brain Injuries; Caliber; Carbon Dioxide; Cell Death; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Collaborations; Complex; Coupling; Dementia; Development; Disease; Ensure; Excision; Functional disorder; Genetic; Glucose; Glutamate Receptor; Goals; Hydrogen-Ion Concentration; Hypercapnia; Hyperemia; Hypocapnia; Impaired cognition; Impairment; Intracranial Pressure; Knowledge; Lead; Measures; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurologic Dysfunctions; Neurons; Nitric Oxide Synthase Type I; Nutrient; Perfusion; Physiological; Pilot Projects; Play; Production; Protons; Regulation; Research Personnel; Resistance; Rest; Role; Site; Stimulus; Synapses; Synaptic plasticity; Testing; Therapeutic; Vascular blood supply; Vascular resistance; Vasodilation; Vasodilator Agents; Work; base; carbonate dehydratase; cardiovascular risk factor; cerebrovascular; extracellular; improved; in vivo; inhibitor/antagonist; innovation; insight; nervous system disorder; novel strategies; overexpression; research study; response; sensor; somatosensory; tool

DESCRIPTION (provided by applicant): Adequate perfusion is essential for normal brain function and impaired regulation of cerebral blood flow (CBF) may contribute to neurological dysfunction and disease. Despite recent progress, our knowledge of mechanisms that regulate CBF remains inadequate. Two of the most powerful stimuli that affect CBF are hypercapnia and increased cellular activity (cellular metabolism and synaptic activity). Both of these stimuli increase local concentrations of hydrogen ion (reduce extracellular pH). The overall goal of this application is to examine the role of acid-sensing ion channels (ASICs) in control of CBF. We found recently that ASICs are required for acid-evoked effects on synaptic plasticity. Moreover, the ASIC1a subtype functions as a chemosensor in neurons mediating hypercapnia- and acid-evoked behaviors. These findings led to preliminary experiments testing whether ASICs also play a role in regulation of CBF. Although effects of hypercapnia and acidosis have been known for decades, mechanisms that initiate vascular responses to these stimuli remain undefined. Based on this background, we propose two Aims. Aim 1 will examine the hypothesis that ASICs mediate vascular responses to hypercapnia. We will examine vascular effects of hypercapnia and acidosis following manipulation of ASICs using genetic and pharmacological approaches. To define the importance of neuronal ASIC, we will take advantage of mice lacking or overexpressing ASIC1a specifically in neurons. We will also use ASIC inhibitors to pharmacologically probe ASIC function. Aim 2 will use similar approaches to examine the hypothesis that neuronal ASICs contribute to vascular responses in models of neurovascular coupling. In pilot studies, we found that disrupting ASIC1a nearly eliminated hypercapnia-induced vasodilation but also significantly attenuated vasodilator responses in a model of neurovascular coupling. Together these studies will unambiguously determine the importance and site of ASIC action in hypercapnia- and proton-dependent regulation of cerebrovascular responses. The studies may provide new and unprecedented insight into the complex interaction between brain and its vascular supply. Such insight may ultimately lead to improved therapeutic approaches for cerebrovascular disease and brain injury. This project was conceived and will be carried out by an innovative collaboration between investigators with diverse expertise in CBF, neurovascular coupling, pH regulation, and ASICs.

描述（由申请人提供）：足够的灌注对于正常的大脑功能至关重要，脑血流（CBF）的调节受损可能导致神经功能障碍和疾病。尽管有最近的进展，但我们对调节CBF的机制的了解仍然不足。影响CBF的两种最强大的刺激是高碳酸盐和增加的细胞活性（细胞代谢和突触活性）。这两种刺激都会增加氢离子的局部浓度（减少细胞外pH）。该应用的总体目标是检查酸性离子通道（ASIC）在控制CBF中的作用。我们最近发现，酸诱发的对突触可塑性的影响需要ASIC。此外，ASIC1A亚型在介导高碳酸和酸诱发的行为的神经元中起作用。这些发现导致初步实验测试ASIC是否在CBF的调节中发挥作用。尽管高碳酸血症和酸中毒的作用已知数十年，但对这些刺激产生血管反应的机制仍然不确定。基于此背景，我们提出了两个目标。 AIM 1将研究ASIC介导血管对高碳酸血管反应的假设。我们将使用遗传和药理学方法来检查ASIC操纵后，高碳酸血管和酸中毒的血管作用。为了定义神经元ASIC的重要性，我们将利用缺乏或过表达ASIC1A的小鼠专门在神经元中。我们还将使用ASIC抑制剂来进行药理学探测ASIC功能。 AIM 2将使用类似的方法来检验以下假设：神经元ASIC在神经血管耦合模型中有助于血管反应。在初步研究中，我们发现破坏ASIC1A几乎消除了高碳酸盐诱导的血管舒张，但在神经血管偶联模型中也显着减弱了血管扩张剂的反应。总之，这些研究将明确确定ASIC作用在脑血管反应的高碳酸和质子依赖性调节中的重要性和部位。这些研究可能会为大脑及其血管供应之间的复杂相互作用提供新的和空前的见解。这种洞察力最终可能导致改善脑血管疾病和脑损伤的治疗方法。该项目是构想的，将由具有CBF，神经血管耦合，pH调节和ASIC的专业知识的研究人员之间的创新合作进行。