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影响1-3%人口的慢性衰弱性疾病。这些疾病的病因是完全未知的。在一个苏格兰家族中，一个主要精神疾病的高度一致性和1号染色体和11号染色体之间的平衡易位，被鉴定为1号染色体上的基因被破坏。对这个家族的五代人进行了染色体组型分析，有这种易位的29名成员中有18人患有精神分裂症、复发性重度抑郁症或双相情感障碍。精神疾病的这种近似孟德尔分离表明，DISC1在维持精神健康方面发挥着不可或缺的作用，而DISC1功能的破坏在精神疾病的病因学中起着重要作用。事实上，DISC1小鼠模型表现出的行为异常让人想起人类疾病的表型，如运动过度、抑郁样行为增加、社交能力和工作记忆下降。其中一些小鼠模型也显示出表明大脑发育受损的脑部病理。最近，我们报道了DISC1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DISC1通过作为GSK32（一种触发2-catenin降解的多效蛋白丝氨酸/苏氨酸激酶）的抑制剂，积极调节Wnt信号通路，从而调节神经祖细胞的增殖。在齿状回中，DISC1功能丧失导致成年神经祖细胞增殖减少，并伴有多动和抑郁样行为增加等行为后果。用GSK3化学抑制剂治疗后，成人神经发生缺陷和异常行为得到逆转。我们的研究结果表明，DISC1在控制GSK32/2-catenin活性中发挥重要作用，而GSK32/2-catenin活性反过来影响神经发生和精神相关行为。在这个应用中，我们建议破译DISC1突变变体如何改变DISC1在Wnt信号传导和神经发生中的作用。我们计划采用多学科方法，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来分析Wnt信号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鉴定和表征小分子探针，用于条件和选择性调节DISC1/GSK32-Wnt/2-catenin途径。这些研究最终将使人们能够更好地了解人类DISC1基因变异与神经发生的影响之间的关系，并更好地了解神经精神疾病的病因和治疗方法。

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.