若干精神分裂症和孤独症新易感基因工程小鼠模型的建立及表型鉴定

Schizophrenia and autism are complex genetic diseases, and are characterized by advanced brain dysfunction.Since the phenotypes observed in vitro are difficult to reflect the clinical features, generating transgenic mice models and estimating their behaviors are of great significance. Although several mouse models were generated based on susceptible genes in the past, it is insufficient to mimic all clinical symptoms and explain the pathogenic mechanism of schizophrenia and autism. On the basis of our previous genetic association study with schizophrenia and autism, this project intends to carry out the following works:1. Generating schizophrenic mouse models (STON2 double mutants knock in mice, OPCML conditional knock out mice) and autistic mouse models (AUTS2 and MEGF10 conditional knock out mice), meanwhile optimizing the model generating condition;2. Applying animal behavior test to evaluate the schizophrenic and autistic like phenotypes of these mice;3. Taking advantage of animal brain imaging, electrophysiology, cellular and molecular biological techniques to carry out intensive gene functional study at the integrate level of animal. The expected result of this project is to provide clues for understanding functions of new schizophrenic and autistic susceptible genes and exploring new drug targets, in the meantime, these mouse models could be shared to the colleagues for their related researches.

精神分裂症和孤独症属于多基因复杂疾病且均表现为高级脑功能障碍，因离体模型难以反映疾病的临床表型，故建立基因工程动物模型并评价其行为有重要意义。虽然既往研究已根据部分易感基因线索制备动物模型，但不足以充分模拟这两种疾病的临床特征并阐释其发病机理。本项目拟在课题组既往对两种疾病遗传关联研究基础上开展如下工作：1.建立精神分裂症(STON2突变基因敲入和OPCML条件性基因敲除)和孤独症(AUTS2和MEGF10条件性基因敲除)小鼠模型，并优化模型的建立条件；2.利用现有行为研究方法系统评价小鼠模型的精神分裂症样和孤独症样特征性行为；3.利用小动物脑成像、电生理以及细胞和分子生物学等技术方法在整体动物水平进行较为深入的功能研究。本项目预期结果将为解析精神分裂症和孤独症的新易感基因功能以及寻找药物治疗新靶点提供线索，构建成功的小鼠模型将提供给国内同行开展相关研究。

精神分裂症和孤独症均属于多基因复杂疾病且表现为高级脑功能障碍，由于细胞模型难以反映疾病的临床表型，因此建立基因修饰动物模型并评价其行为有重要意义。既往研究虽然已根据部分候选基因线索制备小动物模型，但不足以完全解释这两种疾病的临床特征并阐释其发病机制。在本项目的支持下，目前已完成以下几个方面的工作：1.建立精神分裂症(STON2突变基因敲入和Tspan18基因全身敲除)和孤独症(Auts2条件性基因敲除和Pogz全身敲除)等小鼠模型，并优化模型的建立条件；2.利用现有行为研究方法系统评价了小鼠模型的精神分裂症样和孤独症样特征性行为；3.利用光遗传学、电生理、免疫组织化学以及细胞和分子生物学等技术方法在整体动物水平进行较为深入的功能研究。本项目期望为解析精神分裂症和孤独症的新易感基因功能以及寻找药物治疗新靶点提供线索，并依托这些精神分裂症和孤独症小鼠模型与国内同行合作开展其他方面的相关研究。