Chemical Genomic Approaches to Neurobiology of DISC1

DISC1 神经生物学的化学基因组方法

基本信息

批准号：
8409821
负责人：
Li-Huei Tsai
金额：
$ 65.79万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8409821
关键词：
Adult Affect Alleles Alternative Splicing Balanced Chromosomal Translocation Behavior Behavioral Binding Binding Sites Biochemical Biological Assay Bipolar Disorder Brain Brain Pathology Cell Line Cell Proliferation Cells Chemicals Chromosomes, Human, Pair 1 Chronic Collaborations Defect Development Disease Embryo Equilibrium Etiology Exhibits Family Family member Fibroblasts Functional disorder Generations Genes Genetic Variation Genomics Goals Human Human Genetics Hyperactive behavior Impairment In Vitro Incidence Individual Karyotype determination procedure Lead Major Depressive Disorder Maps Mediating Mental Health Mental disorders Methods Mus Nature Neurobiology Neurons Pathway interactions Peptide Library Physiological Play Population Population Control Protein Isoforms Protein-Serine-Threonine Kinases Proteins Recurrence Reporter Reporting Role Schizophrenia Short-Term Memory Signal Pathway Signal Transduction System Testing Transgenic Organisms Variant Viral Work adult neurogenesis axon growth base chemical genetics deep sequencing dentate gyrus depressive symptoms disease phenotype follow-up genetic pedigree genetic variant human disease in vivo in vivo Model induced pluripotent stem cell inhibitor/antagonist insight interdisciplinary approach loss of function member migration mouse model mutant nerve stem cell neurogenesis neuropsychiatry novel novel therapeutics optical imaging overexpression progenitor protein protein interaction public health relevance research study segregation small molecule tool

项目摘要

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.

描述（由申请人提供）：精神分裂症和躁郁症是影响1-3％人口的慢性衰弱疾病。这些疾病的病因是完全未知的。精神分裂症1（DISC1）中断为在苏格兰家族中染色体1上断的基因，具有高度精神疾病的一致性，染色体1和11染色体之间的平衡易位。在这个家庭的五代和18个家族中，karyotyping已完成了该家族的五代和易位的疾病，使其具有SCHIZ RENSILIA的29个成员。这种针对精神疾病的近乎孟德尔的隔离表明，Disc1在维持心理健康中的作用不可或缺，而Disc1功能的破坏在精神疾病的病因中起作用。实际上，盘状小鼠模型表现出行为异常，让人联想到人类疾病表型，例如超倒置，增加抑郁样行为，降低社交性和工作记忆。这些小鼠模型中的几个还显示出脑病理学，指示大脑发育障碍。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通过用作GSK32的抑制剂来调节Wnt信号通路，从而调节神经祖细胞的增殖，GSK32是一种多效性蛋白丝氨酸/苏氨酸激酶，从而触发2-钙蛋白的降解。在齿状回中，椎间盘1的功能丧失导致成人神经祖细胞的增殖减少，伴随着行为后果，包括多动症和抑郁样行为增加。 GSK3化学抑制剂治疗后，成年神经发生缺陷和异常行为逆转。我们的结果表明，Disc1在控制GSK32/2-catenin活性中起着重要作用，这反过来影响神经发生和精神病相关行为。在此应用中，我们建议解释盘1盘突变体的变体如何改变DISC1在Wnt信号传导和神经发生中的作用。我们计划通过对小鼠细胞和体内模型进行研究，以及使用人类细胞分析Wnt信号传导和神经祖细胞发展的实验来采用多学科方法。此外，我们将使用化学遗传学方法来识别和表征小分子探针的条件和选择性调制，以调节盘子1/gsk32-wnt/2-catenin途径。这些研究最终将更好地了解DISC1中人类遗传变异与神经发生的影响之间的关系，并可以更好地了解神经精神疾病的原因和治疗。