Mechanisms of ASIC-mediated neuronal injury

ASIC 介导的神经元损伤机制

基本信息

批准号：
10597668
负责人：
ROGER Pancoast SIMON
金额：
$ 31.31万
依托单位：
MOREHOUSE SCHOOL OF MEDICINE
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：
2017-12-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597668
关键词：
ASIC channel Acidosis Acids Acute Amiloride Attenuated Brain Injuries Brain Ischemia Cations Cause of Death Cell Death Cell surface Data Family Functional disorder Glucose Goals Injury Ion Channel Ions Ischemia Ischemic Brain Injury Ischemic Neuronal Injury Ischemic Stroke Laboratories Mediating Membrane Molecular Morbidity - disease rate Multiple Sclerosis Nature Neurologic Neuronal Injury Neurons Oxygen Pathway interactions Permeability Pharmacotherapy Play Proteins Protons RIPK1 gene Reporting Role Signal Pathway Signal Transduction Signaling Molecule Spinal cord injury Stroke Surface Testing Therapeutic Therapeutic Intervention Toxic effect Trace Elements Traumatic Brain Injury Zinc axonal degeneration cell injury deprivation desensitization disability effective therapy inhibitor member mortality mutant nervous system disorder new therapeutic target novel novel therapeutic intervention pharmacologic public health relevance recruit response side effect stroke intervention success therapeutically effective trafficking

项目摘要

Abstract Ischemic stroke is a leading cause of death and long-term disability. Current drug treatment is limited to tPA, which has a low success rate and potentially severe side effects. Acidosis is a common feature of neurological disorders such as brain ischemia, and it has been shown to play a critical role in stroke. The mechanisms, however, remained elusive. The discovery that protons activate a distinct family of cation channels, the acid-sensing ion channels (ASICs), has shed new light on acid-signaling and acidosis-mediated brain injury. The studies in our laboratories in the past 10 years have provided convincing evidence suggesting that activation of ASIC1a contributes markedly to acidosis-mediated ischemic brain injury. Following our initial report, others have demonstrated an important role for ASIC1a activation in spinal cord injury, traumatic brain injury, and axon degeneration. Thus, ASIC1a represents a novel therapeutic target. Despite its well-established role in neurological disorders, the detailed mechanisms underlying ASIC1a-mediated neuronal injury in stroke remain unclear. We now have strong evidence suggesting that, besides the well-documented Ca2+ toxicity, a combination of increased ASIC1a surface expression, Zn2+ toxicity, and an ion conducting independent cell death pathway participate in ASIC-mediated neuronal injury in ischemia. The objective of this application is to investigate the detailed molecular mechanisms and pathways underlying ASIC-mediated neuronal injury. Given the limitations of currently available pharmacological inhibitors that target these channels, e.g. the non-specificity of amiloride and large molecule nature of PcTX1, the proposed studies may disclose novel and alternative therapeutic strategies for ischemic brain injury.

抽象的缺血性中风是死亡和长期残疾的主要原因。目前药物治疗仅限于 tPA，其成功率较低且可能存在严重副作用。酸中毒是脑缺血等神经系统疾病的常见特征，研究显示在中风中发挥着关键作用。然而，其机制仍然难以捉摸。这发现质子激活一个独特的阳离子通道家族，即酸敏感离子通道（ASIC）为酸信号传导和酸中毒介导的脑损伤提供了新的线索。这过去10年我们实验室的研究提供了令人信服的证据表明 ASIC1a 的激活显着导致酸中毒介导的缺血性脑损伤。根据我们的初步报告，其他人已经证明了 ASIC1a 激活在脊髓损伤、脑外伤和轴突变性。因此，ASIC1a 代表新的治疗靶点。尽管其在神经系统疾病中的作用已得到证实，但详细的 ASIC1a 介导的中风神经元损伤的机制尚不清楚。我们现在有强有力的证据表明，除了有据可查的 Ca2+ 毒性之外， ASIC1a 表面表达增加、Zn2+ 毒性和离子的组合进行独立的细胞死亡途径参与ASIC介导的神经元缺血损伤。本应用的目的是研究详细的分子 ASIC 介导的神经元损伤的机制和途径。鉴于以下限制目前可用的针对这些通道的药物抑制剂，例如非特异性阿米洛利和 PcTX1 的大分子性质，拟议的研究可能会揭示新的和缺血性脑损伤的替代治疗策略。