Neuroprotective role of OGR1 in brain ischemia

项目摘要 脑酸化发生在兴奋性毒性，破坏代谢，并在多种疾病，包括 缺血、多发性硬化和创伤性脑损伤。鉴于酸中毒在疾病中的普遍性， 确定酸信号传导的分子机制将具有广泛的翻译价值。已经 几十年来，酸中毒是神经元损伤的一个关键因素。巧合的是，一个相对 轻度酸中毒可以起到保护作用。近年来，在理解如何 酸中毒导致神经元损伤。这主要是由于酸敏感离子通道（ASIC）的发现， 其是质子门控阳离子通道家族。包括我们在内的一系列数据表明，ASIC是 脑神经元中的主要突触后质子受体，以及酸中毒诱导的神经元损伤的关键介质。 这些关于ASIC的数据极大地推进了我们对酸信号传导的认识。然而，ASIC不会出现 来解释酸中毒的保护作用在我们的初步研究中，我们发现卵巢癌G蛋白 偶联受体1（OGR 1）是一种质子敏感的G蛋白偶联受体（GPCR），广泛表达于人的外周血淋巴细胞中。 个脑袋此外，OGR 1介导海马切片中酸诱导的信号传导。我们的数据进一步表明， OGR 1介导酸中毒和缺血条件下的保护途径。在这里，我们将使用中脑 动脉闭塞，一种广泛用于研究缺血诱导的脑损伤的啮齿动物模型，并确定 OGR 1激活是否导致缺血后的神经保护。为了更好地理解这一机制， 我们将使用体外细胞培养和切片模型来确定介导以下效应的下游信号传导： OGR 1。从拟议的研究中获得的结果将揭示新的保护机制， 细胞外酸信号传导，并为新型治疗药物的设计提供潜在的分子靶点 减轻缺血诱导的脑损伤的方法。

PROJECT ABSTRACT Brain acidification occurs in excitotoxicity, following disrupted metabolism, and in multiple diseases including ischemia, multiple sclerosis, and traumatic brain injury. Given the prevalence of acidosis in disease, determining molecular mechanisms underlying acid signaling will have broad translational value. It has been known for decades that acidosis is one key contributing factor to neuronal injury. Paradoxically, a relatively mild acidosis can be protective. In recent years, a lot of progress has been made on understanding how acidosis leads to neuronal injury. This is largely due to the discovery of acid-sensing ion channels (ASICs), which are a family of proton gated cation channels. A series of data, including ours, show that ASICs are the major postsynaptic proton receptor in brain neurons, and one key mediator of acidosis-induced neuronal injury. These data on ASICs have greatly advanced our knowledge of acid signaling. However, ASICs do not appear to explain the protective effect of acidosis. In our preliminary studies, we found that ovarian cancer G protein coupled receptor 1 (OGR1), a proton-sensitive G protein coupled receptor (GPCR), is widely expressed in the brain. In addition, OGR1 mediates acid-induced signaling in hippocampal slices. Our data further suggest that OGR1 mediates a protective pathway in acidotic and ischemic conditions. Here, we will use middle cerebral artery occlusion, a widely used rodent model for studying ischemia-induced brain injury, and determine whether OGR1 activation leads to neuroprotection following ischemia. To better understand the mechanism, we will use in vitro cell culture and slice models to determine downstream signaling that mediates the effect of OGR1. Results obtained from the proposed study will uncover novel protective mechanisms mediating extracellular acid signaling, and provide potential molecular targets for the design of novel therapeutic approaches to alleviate ischemia-induced brain injury.