神经系统seipin缺失诱发精神迟滞的分子机制研究

项目名称： 神经系统seipin缺失诱发精神迟滞的分子机制研究

项目编号： No.81471157

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈玲

作者单位： 南京医科大学

项目金额： 85万元

中文摘要： 先天性全身脂肪营养不良(CGL)II型是由seipin 基因突变导致脂肪萎缩和精神迟滞(智力低下、情感障碍)为临床特征的常染色体隐性遗传病。seipin基因敲除小鼠发生脂肪减少、抑郁焦虑和认知障碍；脂肪seipin敲除引起脂肪萎缩不伴有精神迟滞；神经seipin敲除可诱发抑郁焦虑和认知障碍，没有脂肪减少。我们首次报道了神经系统seipin缺失诱发精神迟滞。基于①seipin在大脑皮质、海马和下丘脑高表达的特征，②神经seipin缺失导致海马PPARγ低表达、新生神经细胞减少、谷氨酸受体下调和下丘脑内质网应激的预试验结果，本课题将以海马的神经再生、皮层-海马突触结构和功能、下丘脑-垂体-肾上腺皮质轴为切入点，从基础（seipin基因敲除小鼠）到临床（II型CGL患者）系统地研究神经系统seipin缺失诱发智力低下、抑郁和焦虑的机制，确定其关键分子靶点，为II型CGL精神迟滞的治疗提供新策略。

中文关键词： 基因突变；精神迟滞；先天性全身脂肪营养不良；seipin；过氧化物酶体增殖物激活受体γ

英文摘要： Congenital generalized lipodystrophy (CGL) type II by mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene that encodes seipin is characterized by near-total loss of adipose tissue and mental retardation (cognitive deficiency and affective disorders). Our study reported that systemic seipin-deficient (seipin-KO) mice showed severe lipodystrophy, depression-anxiety behaviors and cognitive deficiency. By contrast, fat-specific seipin knockout (seipin-f-KO) mice had generalized lipodystrophy without changes in cognitive and affective behaviors. Neuron-specific seipin knockout (seipin-n-KO) male mice, but not females, appeared cognitive deficiency and affective disorders without lipodystrophy. (1) The seipin is highly expressed in the central nervous system including cortex, hippocampus and hypothalamus. (2) The male seipin-nKO mice showed the reduction of peroxisome proliferator-activated receptor gamma (PPARγ) expression in hippocampus and newly generated neuronal cells with abnormal differentiation of progenitor cells in hippocampal dentate gyrus, dysfunction of glutamate receptor and enhancement of endoplasmic reticulum (ER) stress in hypothalamic neurons. From basic neuroscience (using seipin-KO mice, seipin-f-KO mice and seipin-n-KO mice) to clinical research (CGL-II patients), this study will focuse on exploring influence of lacking seipon on hippocampal neurogenesis, expression and function of glutamate receptors and GABAA receptors, synaptic plasticity, regulation of hypothalamic-pituitary-adrenal (HPA) axis and the underlying mechanisms. Expected outcomes: the identification of molecular mechanisms underlying lack of neuronal seipin leading to mental retardation will provide highly relevant information for treating cognitive deficience and affective disorders in CGL-II patients.

英文关键词： gene mutation;mental retardation;congenital generalized 1ipodystrophy（CGL）;seipin;peroxisome proliferator-activated receptor gamma (PPARγ)