Chemical Genomic Approaches to Neurobiology of DISC1

描述(申请人提供)：精神分裂症和双相情感障碍是慢性衰弱疾病，影响1-3%的人口。这些疾病的病因完全未知。DISC1基因是在一个苏格兰家庭中发现的在1号染色体上被破坏的基因，该家系与严重的精神障碍和1号和11号染色体之间的平衡易位高度一致。该家族的五代人已经进行了染色体核型分析，29名易位成员中有18人患有精神分裂症、反复发作的严重抑郁症或双相情感障碍。这种近乎孟德尔式的精神障碍隔离表明，DISC1在维持精神健康方面发挥了不可或缺的作用，而DISC1功能的中断在精神障碍的病因学中发挥了作用。事实上，DISC1小鼠模型表现出行为异常，使人联想到人类疾病的表型，如多动症、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个也显示出大脑发育受损的大脑病理。最近，我们报道了DISC1在胚胎脑发育和成年神经发生过程中对神经前体细胞增殖的调控。此外，我们发现DISC1通过作为GSK32的抑制剂正向调节Wnt信号通路来调节神经前体细胞的增殖。GSK32是一种多效性蛋白丝氨酸/苏氨酸激酶，可触发2-连环蛋白的降解。在齿状回，DISC1功能丧失导致成年神经前体细胞增殖减少，并伴随着包括多动和抑郁样行为增加的行为后果。用GSK3化学抑制剂治疗后，成人的神经再生缺陷和异常行为被逆转。我们的结果表明，DISC1在控制GSK32/2-连环蛋白活性中起着重要作用，GSK32/2-连环蛋白活性进而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突变体如何改变DISC1在Wnt信号和神经发生中的作用。我们计划采取多学科方法，通过对小鼠细胞和活体模型进行研究，以及包括使用人类细胞来分析Wnt信号和神经前体发育的实验。此外，我们将使用化学遗传学方法来鉴定和表征条件和选择性调节DISC1/GSK32-WNT/2-连环蛋白途径的小分子探针。这些研究最终将使人们更好地了解人类DISC1基因变异与神经发生的影响之间的关系，以及更好地理解神经精神疾病的原因和治疗。 公共卫生相关性：该项目的总体目标是确定人类DISC1变异是否影响Wnt信号和神经干细胞的发展，并使用化学遗传学方法来识别和表征用于条件和选择性调节DISC1/GSK3β/Wnt信号通路的小分子探针。我们相信，这个项目将使我们能够进一步深入了解DISC1的遗传变异如何影响人类细胞中的Wnt信号，这对于阐明DISC1和Wnt信号如何与精神疾病有关是至关重要的。此外，发现能够结合和调节DISC1活性的小分子不仅将为研究人类DISC1的功能提供新的工具，而且还将成为创造旨在调节Wnt信号通路中DISC1功能的新疗法的平台。

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. PUBLIC HEALTH RELEVANCE: The overall goals of this project are to determine if human DISC1 variants affect Wnt signaling and the development of neural stem cells, and to use chemical-genetic approaches to identify and characterize small molecule probes for conditional and selective modulation of the DISC1/GSK3beta/Wnt signaling pathway. We believe that this project will allow us to gain further insight into how genetic variation in DISC1 affects Wnt signaling in human cells, which is imperative to clarifying how DISC1 and Wnt signaling contribute to psychiatric disease. Furthermore, discovering small molecules that can bind and modulate DISC1 activity will not only provide novel tools to study the function of human DISC1, but will also serve as a platform from which to create novel therapeutics aimed at modulating the function of DISC1 in the Wnt signaling pathway.