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

描述(由申请人提供)：充足的血流灌注对正常的大脑功能至关重要，脑血流调节受损可能会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监管机制的了解仍然不足。影响脑血流量的两个最强烈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局部氢离子浓度(降低细胞外pH)。本应用的总体目标是研究酸敏离子通道(ASIC)在控制CBF中的作用。我们最近发现，ASICs是酸诱导突触可塑性所必需的。此外，ASIC1a亚型在神经元中发挥化学感受器的作用，介导高碳酸血症和酸诱发的行为。这些发现导致了初步的实验，测试ASIC是否也在调节CBF中发挥作用。虽然高碳酸血症和酸中毒的影响已经知道几十年了，但启动血管对这些刺激的反应的机制仍然不清楚。基于这一背景，我们提出了两个目标。目的1将检验ASICs介导血管对高碳酸血症反应的假设。我们将使用遗传学和药理学方法研究ASICs操作后高碳酸血症和酸中毒对血管的影响。为了确定神经元ASIC的重要性，我们将利用在神经元中缺乏或过度表达ASIC1a的小鼠。我们还将使用ASIC抑制剂从药理上探讨ASIC的功能。目的2将使用类似的方法来检验神经血管偶联模型中神经元ASIC对血管反应的贡献这一假说。在先导研究中，我们发现，在神经血管偶联模型中，干扰ASIC1a几乎消除了高碳酸血症诱导的血管扩张，但也显著减弱了血管扩张反应。总之，这些研究将明确地确定ASIC在高碳酸血症和质子依赖的脑血管反应调节中的作用的重要性和位置。这些研究可能为了解大脑及其血管供应之间的复杂相互作用提供新的、前所未有的见解。这种洞察力最终可能会改进脑血管疾病和脑损伤的治疗方法。这个项目是由在CBF、神经血管偶联、pH调节和ASIC方面具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。

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.