脑缺血后Homer蛋白调控神经元突起功能重塑的作用及机制研究

Ischemic stroke (IS), with high incidence, is still one of the most common causes of long-term disability in adulthood. Effects of drug treatment and surgical intervention on IS are limited. Recent studies demostrated that IS induced massive apoptosis and necrosis in brain. Especially, neurite damage can lead to disruption in structure and function of nerve conduction. But, its molecular pathological mechanism is not clear, which is the essential reason for high morbidity and mortality. Our previous studies found that Homer, a postsynaptic scaffold protein expressed in the dendritic spines and axon of neurons, was associated with neuronal injury and served as the key point of the molecular network after IS. On the basis of previous studies, this subject is to investigate the mechanism underlying structure and function remodelings of neurite following IS and to elucidate the molecular network and crucial signal pathways related to Homer during repairment of motor, sensory, and cognitive function. Furthermore, our investigation would clarify the molecular network of neurite structure and function remodeling, in which Homer act as a core molecular, and provide a provide a theoretical basis for the design and verification of new strategy on prevention and treatment of IS.

缺血性脑卒中（ischemic stroke, IS）发生率高，是成年人致残的主要原因之一，目前尚无有效的药物治疗手段和外科干预措施。最新研究表明，IS后可引起神经元大量凋亡和坏死，尤其是神经元突起的损伤，可导致神经传导束路结构、功能破坏，但其确切的分子病理机制尚不清楚，这是导致IS后残、死率高的根本原因。我们的前期研究发现，突触后支架蛋白Homer在神经元树突棘和轴浆内特异性表达，参与IS后神经元损伤过程，是其分子调控网络的关键点。本课题拟在以往工作基础上，深入研究Homer对IS后神经元突起结构和功能重塑的调控作用与机制，阐明Homer参与IS后运动、感觉、认知功能损伤与修复过程的分子机制与重要信号途径，进而以Homer为核心揭示IS后神经元突起损伤与功能重塑的分子调控网络，为设计和验证IS的预防和治疗新策略提供理论依据。

随着世界范围内人口老龄化的加剧，缺血性脑卒中（Ischemic Stroke, IS）发生率逐年增高，成为威胁人类健康的“三大杀手”之一。IS可直接引起脑组织严重受损，导致神经细胞坏死；随后产生的继发性脑损害可通过炎症、氧化应激等多种途径诱发坏死区周围神经细胞凋亡。在尽可能减少神经细胞损伤的前提下，如何能够更加有效的促进存活的神经细胞发挥原有的神经功能，是目前IS研究亟待解决的关键问题。本课题在以往工作基础上，利用基因编辑小鼠、疾病动物模型、慢病毒转染等方法，深入研究Homer蛋白对IS后神经元突起结构和功能重塑的调控作用与机制，阐明Homer蛋白参与IS后运动、认知功能损伤与修复过程的分子机制与重要信号途径，进而以Homer为核心揭示IS后神经元突起损伤与功能重塑的分子调控网络，为促进 IS后神经功能恢复奠定理论基础。通过本项目的研究，我们发现了在IS后Homer能够差异性调控MAPK和PTEN/mTOR信号途径，进而影响神经元树突和轴突在IS后的功能改变；以Homer蛋白为靶点可以促进IS后的神经功能恢复，从而发挥脑保护效应。基于以上研究结果，我们首次以突触后支架蛋白Homer为切入点，系统阐述了IS后神经元突起结构与功能改变的时空规律及其与神经功能损害之间的关系，探讨不同Homer蛋白调控神经元突起功能重塑的机制及其下游分子网络。同时，我们首次通过分析Homer蛋白与下游分子的相互作用潜在位点，探索设计小分子多肽或化合物作为临床神经保护药物研发候选靶点的可能性，为 IS 后神经元转归及神经保护作用的研究提供新思路和新方法。