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。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，除了有充分记录的钙毒性外， ASIC1a表面表达增加、锌毒性和一种离子的组合 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。

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.