Neuroprotective role of OGR1 in brain ischemia

OGR1在脑缺血中的神经保护作用

基本信息

批准号：
9470605
负责人：
Xiangming Zha
金额：
$ 37.46万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9470605
关键词：
ASIC channel Acidosis Acids Alteplase Attenuated Brain Brain Injuries Brain Ischemia Brain region Calcium Cations Cell Culture Techniques Cells Complex Corpus striatum structure Coupled Cyclic AMP Cytoplasmic Granules Data Diglycerides Disease Equilibrium FDA approved Family G-Protein-Coupled Receptors GPR4 gene GPR68 gene Hippocampus (Brain)Image In Vitro Infarction Injury Ion Channel Ischemia Knowledge Lead Mediating Mediator of activation protein Metabolism Methods Middle Cerebral Artery Occlusion Mitochondria Modeling Molecular Molecular Target Multiple Sclerosis Mus N-Methyl-D-Aspartate Receptors Neuronal Injury Neurons Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Prevalence Process Property Protein Kinase C Protons Reagent Regulation Rodent Model Role Series Signal Transduction Slice Spinal Ganglia Stroke Study models System Testing Therapeutic Intervention Traumatic Brain Injury base design disability excitotoxicity experimental study extracellular hippocampal pyramidal neuron mitochondrial permeability transition pore mortality neuroprotection new therapeutic target novel novel therapeutic intervention overexpression postsynaptic protective effect receptor relating to nervous system sensor stroke treatment

项目摘要

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.

项目摘要脑酸化发生在兴奋性中毒、新陈代谢紊乱以及多种疾病中，包括缺血、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，确定酸信号传导的分子机制将具有广泛的转化价值。它一直几十年来，人们都知道酸中毒是神经元损伤的关键因素之一。矛盾的是，相对轻度酸中毒可以起到保护作用。近年来，在理解如何酸中毒会导致神经元损伤。这很大程度上归功于酸敏离子通道（ASIC）的发现，它们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 是脑神经元中主要的突触后质子受体，也是酸中毒引起的神经元损伤的关键介质之一。这些有关 ASIC 的数据极大地增进了我们对酸性信号传导的了解。然而，ASIC并没有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) 是一种质子敏感的 G 蛋白偶联受体 (GPCR)，广泛表达于脑。此外，OGR1 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 OGR1 在酸中毒和缺血条件下介导保护途径。在这里，我们将使用中脑动脉闭塞，一种广泛使用的啮齿动物模型，用于研究缺血引起的脑损伤，并确定 OGR1 激活是否会导致缺血后的神经保护。为了更好地理解该机制，我们将使用体外细胞培养和切片模型来确定介导作用的下游信号传导奥格鲁1。从拟议的研究中获得的结果将揭示介导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缓解缺血引起的脑损伤的方法。