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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