Aldoc乳酰化修饰促进星形胶质细胞活化及其在脑缺血脑损伤中的作用及机制研究

揭示脑缺血后星形胶质细胞（As）活化机制，降低其所致的神经元死亡加速，延长血管开通有效时间窗，有望救治更多急性脑梗死患者。脑缺血后乳酸大量堆积，提示糖酵解增强产生ATP可能为As活化提供能量。最新研究发现，乳酸可作为乳酰化修饰（Kla）底物，调控蛋白功能。我们预实验利用Kla定量质谱检测发现，缺血皮层糖酵解限速酶Aldoc-Kla显著增加。结合研究发现Aldoc可通过调控肿瘤细胞骨架重塑影响其迁移，且主要表达于As，我们推测：脑缺血后Aldoc-Kla通过促进细胞骨架重塑及增强糖酵解，促进As活化，加速神经元死亡。本项目拟采用基因编辑、分子生物学等研究手段，阐明脑缺血后Aldoc-Kla增加在As活化中的作用机制。该研究不仅可从全新Kla角度揭示脑缺血后As活化机制，还有望通过干预Aldoc-Kla抑制其活化，提高神经元存活率，延长血管开通时间窗，为救治更多急性脑梗死患者提供新思路新策略。

Uncovering the activation mechanism of astrocytes after cerebral ischemia to reduce the acceleration of neuronal death could significantly extend the effective time window of revascularization, which is expected to save more patients with acute ischemic stroke. The massive accumulation of lactic acid after cerebral ischemia suggested that the production of ATP by enhanced glycolysis might provide energy for the activation of astrocytes after cerebral ischemia. Recent study has found that lactic acid can be used as a reaction substrate for lactylation (Kla) to regulate the function of proteins. We preliminary performed the experiment of Quantitative global proteome and Lysine Lactylation Identification, and found that the glycolytic rate-limiting enzyme Aldoc-Kla significantly increased in ischemic cortex. In combination with previous reported results that Aldoc could affect the tumor cell migration by regulating the cytoskeleton remodeling, and Aldoc was mainly expressed in astrocytes. Therefore, we speculated that Aldoc-Kla may promote the activation of astrocytes by inducing cytoskeletal remodeling and enhancing glycolysis to accelerate the death of neurons after cerebral ischemia. This project will use gene editing, molecular biology and other research methods to elucidate the mechanism of Aldoc-Kla increase in the activation of astrocytes after cerebral ischemia. This study not only reveals the activation mechanism of astrocytes after cerebral ischemia from a new perspective of lactylation, but also is expected to improve the neuronal survival and extends the time window of revascularization by interfering with Aldoc-Kla to inhibit astrocyte activation, which provide new ideas and strategies for the treatment of more patients with acute ischemic stroke.