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，即精神障碍中的缺失和复制。大规模的基因组调查显示，染色体1q21.1和15q13.3上的缺失与精神分裂症之间存在关联，优势比为7到18。我们现在建议使用染色体工程来建立两个精神分裂症的临床前病因学模型，以在小鼠胚胎干细胞和活体动物中模拟这些半合子缺失。携带与精神分裂症患者相同的半合子缺失的小鼠将接受初步的行为特征，重点是检查感觉运动门控和工作记忆缺陷，有望成为研究精神分裂症强烈风险因素的表型潜力，特别是潜在风险增加的生物机制的有价值的工具。 公共卫生相关性：精神分裂症是一种严重的精神疾病，影响着全球约1%的人口，但我们对这种疾病的发病机制的了解极其有限。基于人类大规模的全基因组调查，确定了染色体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在小鼠中模拟这些半合子缺失，产生两个新的精神分裂症病因学模型。对这些小鼠的检查将对增加我们对该病的发病机制和病理生理学的了解以及开发新的治疗策略具有重要意义。

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.