Neuroprotective role of OGR1 in brain ischemia

项目摘要 大脑酸化在代谢紊乱后出现兴奋性毒性，并在多种疾病中发生，包括 脑缺血、多发性硬化症和创伤性脑损伤。鉴于酸中毒在疾病中的普遍存在， 确定酸信号的分子机制将具有广泛的翻译价值。一直以来 几十年来，人们就知道酸中毒是导致神经元损伤的一个关键因素。矛盾的是，一个相对 轻微的酸中毒可以起到保护作用。近几年来，在理解人类如何 酸中毒会导致神经元损伤。这在很大程度上是由于酸敏离子通道(ASIC)的发现， 这是一个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 脑神经元中主要的突触后质子受体，也是酸中毒引起神经元损伤的关键介质之一。 这些关于ASIC的数据极大地促进了我们对ACID信号的了解。但是，ASIC不会出现 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(OGR1)是一种质子敏感型G蛋白偶联受体，广泛表达于 大脑。此外，OGR1在海马片中介导酸诱导的信号转导。我们的数据进一步表明， 在酸性和缺血条件下，OGR1介导了一种保护途径。这里，我们将使用中脑 动脉阻塞是一种广泛用于研究脑缺血所致脑损伤的啮齿动物模型，并确定 OGR1激活是否导致脑缺血后的神经保护。为了更好地理解这种机制， 我们将使用体外细胞培养和切片模型来确定下游信号转导机制。 OGR1。拟议的研究结果将揭示新的保护机制， 胞外酸信号转导，并为新型治疗药物的设计提供潜在的分子靶点 减轻脑缺血损伤的方法。

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.