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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.

摘要缺血性中风是导致死亡和长期残疾的主要原因。现行药品治疗仅限于tPA，其具有低成功率和潜在的严重副作用。酸中毒是神经系统疾病如脑缺血的常见特征，并且已经被在中风中起关键作用。然而，这些机制仍然难以捉摸。的发现质子激活一个独特的阳离子通道家族，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。的过去10年来，我们实验室的研究提供了令人信服的证据，表明 ASIC1a的激活显著促进酸中毒介导的缺血性脑损伤。在我们的初步报告之后，其他人已经证明了ASIC1a激活在脊髓损伤、创伤性脑损伤和轴突变性。因此，ASIC1a代表新的治疗靶点。尽管它在神经系统疾病中的作用已经确立，但详细的中风中ASIC1a介导的神经元损伤的潜在机制仍不清楚。我们现在有强有力的证据表明，除了记录良好的Ca2+毒性，增加的ASIC1a表面表达、Zn 2+毒性和离子毒性的组合传导独立的细胞死亡通路参与ASIC介导的神经元凋亡缺血损伤。本申请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。的限制条件下目前可获得的靶向这些通道的药理学抑制剂，例如非特异性阿米洛利和大分子性质的PcTX1，拟议的研究可能会揭示新的，缺血性脑损伤的替代治疗策略。