Mechanisms of ASIC-mediated neuronal injury

ASIC 介导的神经元损伤机制

• 批准号: 10440235
• 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
• 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/10440235
• 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; Ions; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Ischemic Stroke; Laboratories; Lead; Light; Mediating; Membrane; Molecular; Morbidity - disease rate; Multiple Sclerosis; Nature; Neurologic; Neuronal Injury; Neurons; Oxygen; Pathway interactions; Permeability; Pharmacology; 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; public health relevance; recruit; response; side effect; stroke intervention; success; therapeutically effective; trafficking

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。当期药物 治疗仅限于tPA，成功率低，可能有严重的副作用。 酸中毒是脑缺血等神经疾病的常见特征，而且一直以来 被证明在中风中起着关键作用。然而，这些机制仍然难以捉摸。这个 发现质子激活了一种独特的阳离子通道家族，即酸敏感离子 通道(ASICs)，为酸信号和酸中毒介导的脑损伤提供了新的线索。这个 我们实验室过去10年的研究提供了令人信服的证据，表明 ASIC1a的激活在酸中毒所致的缺血性脑损伤中起重要作用。 在我们最初的报告之后，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代表一个 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 ASIC1a介导的卒中神经元损伤机制尚不清楚。我们现在 有强有力的证据表明，除了有充分证据证明的钙毒性外， ASIC1a表面表达增加、锌毒性和一个离子的组合 独立的细胞死亡通路参与ASIC介导的神经元 缺血损伤。这项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， 目前可用的以这些通道为靶点的药物抑制剂，例如非特异性 关于阿米洛利和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。