星形胶质细胞LRP4通过调控TSP1表达影响海马神经元树突棘形成作用机制

项目名称： 星形胶质细胞LRP4通过调控TSP1表达影响海马神经元树突棘形成作用机制

项目编号： No.31460260

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 王顺启

作者单位： 南昌大学

项目金额： 48万元

中文摘要： LRP4是神经肌肉接头（NMJ）形成中发挥重要作用的穿膜蛋白，但其在中枢神经系统的表达和功能尚不明确。我们预实验发现，LRP4在星形胶质细胞特异性高表达；在GFAP-Cre介导的条件性LRP4基因敲除小鼠中，与神经元树突棘发育相关的星形胶质细胞分泌因子TSP1表达显著减少，同时海马区锥体神经元树突棘密度显著降低。我们推测，LRP4通过TSP1调节锥体神经元树突棘发育。为此，本项目将在原代缺失LPR4星形胶质细胞中，通过过表达LRP4全长或配体结合结构域缺失突变体观察对TSP1表达的改变，从而探索LRP4与配体结合是否调节TSP1的表达。进一步在星形胶质细胞与海马神经元共培养模型中，研究LRP4对TSP1的调节是否影响树突棘的发育。最后在突变小鼠体内验证体外结果。本研究揭示中枢神经系统LRP4调节树突棘形成的新的分子机制，为治疗突触异常的神经系统疾病提供理论基础。

中文关键词： 星形胶质细胞；锥体神经元；树突棘；低密度脂蛋白受体相关蛋白LRP4；血小板反应蛋白TSP1

英文摘要： LRP4 is crucial for formation1 of the neuromuscular junction (NMJ). However, little is known about its expression and roles in the central nervous system (CNS). Intriguingly, in our preliminary experiments, we found that LPR4 is expressed highly and exclusively to astrocytes in the CNS. Moreover, in the hippocampus of GFAP-Cre mediated conditional LRP4 knockout (GFAP-Cre; LRP4f/f) mice, the levels of TSP1, a positive regulator of spine formation secreted by the astrocytes, and the dendritic spine density of pyramidal neurons are significantly decreased. We therefore hypothesized that LRP4 modulates the dendritic spine formation of pyramidal neurons through regulation of TSP1 expression in the astrocytes. In our study, we will observe whether the interaction between LPR4 and its ligand is involved in its regulation of TSP1 expression by overexpressing the wild type or ligand-binding domain deletion mutant of LRP4 in the primary astrocytes of GFAP-Cre;LRP4f/f mice. Furthermore, we will investigate whether the regulation of TSP1 expression by LPR4 plays a role in the dendritic spine development by using astrocytes and neurons co-culture system. Finally, we will verify the mechanism underlying the regulation of dendritic spine development by LRP4 in the GFAP-Cre;LRP4f/f mice. This study will disclose a novel function of LRP4 in the CNS, and will also be helpful for understanding of some neurological diseases with abnormal synapses.

英文关键词： Astrocyte;Pyramidal Neuron;Spine;LRP4;TSP1