Generation of etiological models for schizophrenia by chromosome engineering

描述（由申请人提供）：最近发现了拷贝数变异（CNV）的相关性，即精神疾病中的缺失和重复。大规模的基因组调查显示，染色体1q21.1和15q13.3的缺失与精神分裂症之间存在关联，比值比为7至18。我们现在提出了两个临床前的精神分裂症的病因模型，利用染色体工程来模拟这些小鼠胚胎干细胞和活动物的半合子缺失。携带半合子缺失的小鼠对应于那些发现在精神分裂症患者将经历一个初始的行为特征，重点是检查感觉运动门控和工作记忆缺陷，并有望成为有价值的工具，调查精神分裂症的强危险因素的表型潜力，特别是这种增加的风险的生物学机制。 公共卫生相关性：精神分裂症是一种严重的精神障碍，影响了全世界约1%的人口，但我们对这种疾病的发病机制的了解非常有限。基于人类大规模全基因组调查确定染色体1q21.1和15q13.3上的特定拷贝数变异与精神分裂症之间的关联，我们将使用染色体工程建模这些小鼠中的半合子缺失来产生两种新的精神分裂症病因模型。这些小鼠的检查将是重要的，以增加我们对疾病的发病机制和病理生理学的理解，并为新的治疗策略的发展。

DESCRIPTION (provided by applicant): The relevance of copy number variations (CNVs), i.e. deletions and duplications in psychiatric disorders has recently been discovered. Large-scale genome surveys show an association between deletions on chromosomes 1q21.1 and 15q13.3 and schizophrenia with odds ratios of 7 to 18. We now propose generating two preclinical etiological models of schizophrenia using chromosome engineering to model these hemizygous deletions in murine embryonic stem cells and live animals. Mice carrying hemizygous deletions corresponding to those found in schizophrenic patients will undergo an initial behavioral characterization with an emphasis on examining sensorimotor gating and working memory deficits and are expected to be valuable tools for investigating the phenotypic potential of strong risk factors of schizophrenia and in particular the biological mechanisms underlying this increased risk. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe mental disorder affecting approximately 1% percent of the population worldwide but our knowledge about the pathogenesis of the disease is critically limited. Based on human large-scale genome-wide surveys identifying an association between specific copy number variations on chromosomes 1q21.1 and 15q13.3 and schizophrenia, we will generate two novel etiological models of schizophrenia using chromosome engineering modeling these hemizygous deletions in mice. Examination of these mice will be important for increasing our understanding of the pathogenesis and pathophysiology of the disease and for the development of novel treatment strategies.