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

基本信息

批准号：
8285454
负责人：
Frank M Faraci
金额：
$ 37.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/8285454
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Optimal regulation of cerebral blood flow is critical for brain function. Abnormalities in the control of cerebral blood flow lead to brain dysfunction and even cell death. The goal of these studies is to further elucidate mechanisms that regulate brain blood flow but examining the role of acid-sensing ion channels in the control of cerebral blood flow. These studies will provide new insight into the complex interaction between brain and its vascular supply. Such knowledge may ultimately lead to improved therapeutic approaches for cerebrovascular disease and brain injury.

描述（由申请人提供）：充足的灌注对于正常的脑功能至关重要，脑血流（CBF）调节受损可能导致神经功能障碍和疾病。尽管最近取得了进展，但我们对 CBF 调节机制的了解仍然不足。影响 CBF 的两个最强大的刺激是高碳酸血症和细胞活动增加（细胞代谢和突触活动）。这两种刺激都会增加氢离子的局部浓度（降低细胞外 pH 值）。该应用的总体目标是检查酸敏离子通道 (ASIC) 在 CBF 控制中的作用。我们最近发现，酸诱发的突触可塑性效应需要 ASIC。此外，ASIC1a 亚型在神经元中充当化学传感器，介导高碳酸血症和酸诱发的行为。这些发现引发了初步实验，测试 ASIC 是否也在 CBF 调节中发挥作用。尽管高碳酸血症和酸中毒的影响已为人所知数十年，但引发血管对这些刺激反应的机制仍不清楚。基于这样的背景，我们提出两个目标。目标 1 将检验 ASIC 介导血管对高碳酸血症反应的假设。我们将检查使用遗传和药理学方法操作 ASIC 后高碳酸血症和酸中毒对血管的影响。为了定义神经元 ASIC 的重要性，我们将利用神经元中缺乏或过度表达 ASIC1a 的小鼠。我们还将使用 ASIC 抑制剂来药理学探测 ASIC 功能。目标 2 将使用类似的方法来检验神经元 ASIC 对神经血管耦合模型中的血管反应做出贡献的假设。在初步研究中，我们发现破坏 ASIC1a 几乎消除了高碳酸血症引起的血管舒张，但也显着减弱了神经血管耦合模型中的血管舒张反应。这些研究将共同明确确定 ASIC 在高碳酸血症和质子依赖性脑血管反应调节中的重要性和作用部位。这些研究可能为大脑及其血管供应之间复杂的相互作用提供新的、前所未有的见解。这种见解最终可能会改进脑血管疾病和脑损伤的治疗方法。该项目是由在 CBF、神经血管耦合、pH 调节和 ASIC 领域拥有不同专业知识的研究人员之间的创新合作构思和实施的。公共卫生相关性：脑血流的最佳调节对于大脑功能至关重要。脑血流控制异常会导致脑功能障碍，甚至细胞死亡。这些研究的目的是进一步阐明调节脑血流的机制，同时检查酸敏感离子通道在控制脑血流中的作用。这些研究将为大脑及其血管供应之间复杂的相互作用提供新的见解。这些知识最终可能会改进脑血管疾病和脑损伤的治疗方法。