IGF1调节脆性X综合症模型小鼠神经元发育及突触可塑性异常的作用及其机制研究

项目名称： IGF1调节脆性X综合症模型小鼠神经元发育及突触可塑性异常的作用及其机制研究

项目编号： No.81503046

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 冯斌

作者单位： 中国人民解放军第四军医大学

项目金额： 17.9万元

中文摘要： 脆性X综合症（FXS）是一种常见的伴性遗传智力发育障碍疾病，影响着1/2500-1/4000的人口，目前临床上仍缺乏有效治疗药物，新的靶点亟待挖掘。胰岛素样生长因子1（IGF1）是一个由70个氨基酸组成的生长激素，在中枢神经系统具有促神经存活，树突生长，突触再生等重要作用。我们的研究显示，FXS模型小鼠神经元树突发育和突触形成均出现障碍，同时其血清及脑内海马区IGF1水平显著减少，海马区IGF1受体及其下游接头分子IRS1表达水平显著降低。然而，IGF1是否参与了FXS神经元发育和突触可塑性异常的调节及其可能的分子机制仍不清楚。本项目将以FMR1 基因敲除小鼠为研究模型，采用分子生物学、电生理学、形态学、药理学和行为学等手段，以期阐明 IGF1水平降低在FXS神经元发育及突触可塑性异常中的作用及其机制，发掘潜在的药物干预性靶点，可望为FXS的临床综合治疗提供新的方向和理论依据。

中文关键词： 脆性X综合症；胰岛素样生长因子1；电生理学；突触可塑性；发育

英文摘要： Fragile X syndrome (FXS) is an X-linked disorder and is the most common form of inherited intellectual disability, estimated to affect between 1/2500 and 1/4000 individuals. By now, there is still no effective drug for this disease, so it is urgent to find a new target. Insulin-like growth factor 1 (IGF1) is a growth hormone, composed of 70 amino acids, and in the central nervous system, it plays important roles in promoting neuron growth, dendritic arborization and synaptogenesis. Our studies have found that dendritic development and synaptogenesis was abnormal in the primary cultured neurons of FXS mice, and IGF1 level in the serum and hippocampus decreased significantly, so did the levels of IGF1R and its adaptor protein IRS1 in the hippocampus. However, it is unclear whether IGF1 regulates the aberrant neuron development and synaptic plasticity of FXS, and what is the underlying mechanisms. In this project, we will take FMR1 knockout mice as the research model, and anticipate to clarify the effects and mechanisms of reduction of IGF1 level of FXS mice on the neuron development and synaptic plasticity by using molecular biology, electrophysiology, morphology, pharmacology and behavioral test. According to this project, we anticipate to find an effective drug target and provide a new direction and theoretical basis for clinical therapy of FXS.

英文关键词： fragile X syndrome;insulin-like growth factor 1;electrophysiology; synaptic plasticity;development