缺血区组织酸化是中风后神经元死亡的主要原因之一。申请人所在课题组近期报道酸敏感离子通道1a（ASIC1a）通过其胞内C-端构象变化偶联受体结合蛋白1（RIP1）磷酸化介导缺血后神经元程序性坏死。预实验结果显示ASIC1a N-端部分序列具有神经保护作用，且与抑制C-端特定序列CP-1有关。在本项目中，我们将通过CRISPR-Cas9技术构建ASIC1a离子通道功能缺失的HIF-ASIC1a小鼠和保留通道功能而C端功能缺失的RC-ASIC1a小鼠，阐明ASIC1a非通道功能参与中风后神经元程序性坏死及其信号通路，揭示ASIC1a N-端神经保护的具体机制，以N-端氨基酸序列设计筛选小分子神经保护肽，并在动物中风模型中验证。该项目将深化和扩展ASIC1a在缺血性神经元死亡中的作用机理，并以ASIC1a为靶点探索新型小分子神经保护肽，推动基础研究向临床转化方向发展，促进中风治疗新药的开发。

Acidotoxicity is one of the leading causes of neuron death after ischemic stroke. Recently, we have demonstrated that extracellular protons trigger neuronal necroptosis via acid-sensing ion channel 1a (ASIC1a), but independent of its ion-conducting function. Acid stimulation recruits receptor-interacting protein 1 (RIP1) to the ASIC1a C-terminus, causing RIP1 phosphorylation and subsequent neuronal necroptosis. Our unpublished data further showed that ASIC1a N-terminus has neuroprotective effects via interaction with its C-terminus, which may indicate novel mechanisms underlying necroptosis. In this project, we aim at confirming the non-ion channel function of ASIC1a in neuronal necroptosis after ischemic stroke by using ASIC1a mutant mice, investigating the signaling pathways, screening and identifying the neuroprotective peptides targeting ASIC1a. The project will enrich and extend the role of ASIC1a in ischemic neuronal cell death, develop new neuroprotective peptides and promote the translational research of ASIC1a channels, which may result in therapeutic drugs for stroke therapy.