Chemical Genomic Approaches to Neurobiology of DISC1

描述（由申请人提供）：精神分裂症和双相情感障碍是慢性衰弱性疾病，影响1-3%的人口。这些疾病的病因完全未知。Disrupted in Schizophrenia-1（DISC 1）被鉴定为在一个苏格兰家族中1号染色体上被破坏的基因，该家族具有高度一致的主要精神疾病和1号和11号染色体之间的平衡易位。对这个家族的五代人进行了核型分析，29名易位成员中有18名患有精神分裂症、复发性重度抑郁症或双相情感障碍。精神疾病的这种类型的近孟德尔隔离表明DISC 1在维持心理健康中的不可或缺的作用，DISC 1功能的破坏在精神疾病的病因学中起作用。事实上，DISC 1小鼠模型表现出令人联想到人类疾病表型的行为异常，如运动过度、抑郁样行为增加、社交能力和工作记忆下降。这些小鼠模型中的几种还显示出指示脑发育受损的脑病理学。最近，我们报道了DISC 1在胚胎脑发育和成人神经发生过程中调节神经祖细胞的增殖。此外，我们发现DISC 1通过作为GSK 32（一种触发2-连环蛋白降解的多效性蛋白丝氨酸/苏氨酸激酶）的抑制剂正向调节Wnt信号通路来调节神经祖细胞增殖。在齿状回中，DISC 1功能丧失导致成年神经祖细胞增殖减少，这伴随着行为后果，包括多动症和抑郁样行为增加。用GSK 3化学抑制剂治疗后，成年神经发生缺陷和异常行为被逆转。我们的研究结果表明，DISC 1在控制GSK 32/2-catenin活性方面起着重要作用，而GSK 32/2-catenin活性反过来又影响神经发生和精神病相关行为。在本申请中，我们建议破译DISC 1突变变体如何改变DISC 1在Wnt信号传导和神经发生中的作用。我们计划采取多学科的方法，通过小鼠细胞和体内模型进行研究，以及包括使用人类细胞分析Wnt信号传导和神经祖细胞发育的实验。此外，我们将使用化学遗传学方法来识别和表征DISC 1/GSK 32-Wnt/2-catenin通路的条件性和选择性调节的小分子探针。这些研究最终将使我们能够更好地了解人类DISC 1基因变异与神经发生之间的关系，并更好地了解神经精神疾病的病因和治疗。

DESCRIPTION (provided by applicant): Schizophrenia and bipolar disorder are chronic debilitating disorders that affect 1-3% of the population. The etiology of these disorders is completely unknown. Disrupted in Schizophrenia-1 (DISC1) was identified as the gene that was disrupted on chromosome 1 in a Scottish family with a high concordance of major psychiatric disorders and a balanced translocation between chromosomes 1 and 11. Karyotyping has been done on five generations of this family and 18 of the 29 members with this translocation have schizophrenia, recurrent major depression, or bipolar disorder. This type of near Mendelian segregation for psychiatric disorders indicates an integral role for DISC1 in maintaining mental health and that disruption of DISC1 functions plays a role in the etiology of psychiatric disorders. Indeed, DISC1 mouse models exhibit behavioral abnormalities reminiscent of human disease phenotypes such as hyperlocomotion, increased depressive-like behavior, decreased sociability and working memory. Several of these mouse models also display brain pathology indicative of impairment in brain development. Recently, we reported that DISC1 regulates the proliferation of neural progenitors during embryonic brain development and adult neurogenesis. Furthermore, we discovered that DISC1 regulated neural progenitor proliferation by positively regulating the Wnt signaling pathway by acting as an inhibitor of GSK32, a pleiotropic protein serine/threonine kinase that triggers the degradation of 2-catenin. In the dentate gyrus, DISC1 loss of function causes reduced proliferation of adult neural progenitors, which is accompanied by behavioral consequences including hyperactivity and increased depressive-like behavior. The adult neurogenesis defects and abnormal behavior were reversed upon treatment with a GSK3 chemical inhibitor. Our results indicate that DISC1 plays an important role in controlling GSK32/2-catenin activity, which in turn impacts neurogenesis and psychiatric-related behaviors. In this application, we propose to decipher how DISC1 mutant variants may alter the role of DISC1 in Wnt signaling and neurogenesis. We plan to take a multidisciplinary approach by performing studies with mouse cell and in vivo models, as well as including experiments using human cells to analyze Wnt signaling and neural progenitor development. Furthermore, we will use chemical-genetic approaches to identify and characterize small-molecule probes for conditional and selective modulation of the DISC1/GSK32-Wnt/2-catenin pathway. These studies will ultimately enable a better understanding of the relationship between human genetic variation in DISC1 and the effects on neurogenesis, as well as to lead to a better understanding of the causes and treatment of neuropsychiatric disease.