Mechanisms of ASIC-mediated neuronal 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。

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.