Neuroprotective role of OGR1 in brain ischemia

OGR1在脑缺血中的神经保护作用

• 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
• 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

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 大脑酸化发生在兴奋性毒性中，新陈代谢中断以及多种疾病（包括） 缺血，多发性硬化症和创伤性脑损伤。鉴于疾病中酸中毒的患病率 确定酸信号传导基础的分子机制将具有广泛的翻译值。它一直 几十年来，酸中毒是导致神经元损伤的关键因素之一。矛盾的是，一个相对 温和的酸中毒可以具有保护作用。近年来，在理解如何 酸中毒会导致神经元损伤。这主要是由于发现了酸性离子通道（ASIC）， 这是质子门控阳离子通道的家族。一系列数据，包括我们的数据，表明ASIC是 脑神经元中主要的突触后质子受体，以及酸中毒引起的神经元损伤的一个关键介体。 这些有关ASIC的数据极大地提高了我们对酸信号传导的了解。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 耦合受体1（OGR1），一种质子敏感的G蛋白偶联受体（GPCR），在在 脑。另外，OGR1介导了海马切片中酸诱导的信号传导。我们的数据进一步表明 OGR1在酸性和缺血性条件下介导了保护性途径。在这里，我们将使用中大脑 动脉阻塞，一种用于研究缺血诱导脑损伤的广泛使用的啮齿动物模型，并确定 OGR1激活是否导致缺血后神经保护。为了更好地理解机制， 我们将使用体外细胞培养和切片模型来确定介导的下游信号传导 OGR1。从拟议的研究中获得的结果将发现介导的新型保护机制 细胞外酸信号传导，并为新型治疗设计提供了潜在的分子靶标 减轻缺血引起的脑损伤的方法。