Functional Analysis of Schizophrenia-Associated Genes

精神分裂症相关基因的功能分析

• 批准号: 9931721
• 负责人: Summer B Thyme
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9931721
• 关键词: Affect; Anatomy; Animals; Atlases; Behavior; Behavioral; Biological Models; Brain; Candidate Disease Gene; Cerebellum; Defect; Development; Disease; Foundations; Genes; Genetic; Genomic Segment; Genomics; Goals; Image; Link; Location; Locomotion; Mental disorders; Mentors; Modeling; Molecular; Monitor; Motor; Movement; Neurons; Pathway interactions; Phase; Phenotype; Population; Process; Prosencephalon; Reagent; Resolution; Role; Schizophrenia; Structure; Systems Analysis; Testing; Zebrafish; base; behavior test; experience; gene function; genome editing; genome wide association study; genome-wide; improved; inhibitory neuron; loss of function; mutant; neurodevelopment; neuron development; novel; novel diagnostics; novel therapeutics; prepulse inhibition; relating to nervous system; screening; skills; tool; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate the functions of schizophrenia-associated genes using zebrafish as a model system. Large-scale genome-wide association studies have begun to uncover numerous candidate genes linked to schizophrenia. Yet it remains unclear how these genes function and how they contribute to the underlying molecular, cellular, developmental and behavioral processes disrupted in the disorder. Recent technological breakthroughs in zebrafish – targeted genome editing, whole-brain activity imaging, brain atlas registration, behavioral profiling – combined with the ease of studying large numbers of animals make it an ideal system for analyzing psychiatric disease genes. Preliminary studies led to the creation of zebrafish mutants for 96 schizophrenia-associated genes. Characterization of 59 of these mutants for altered brain anatomy and activity has revealed 27 mutants with phenotypical abnormalities. In particular, ZNF536, a schizophrenia-associated transcription factor, was found to be involved in the development of GABAergic inhibitory neurons in the forebrain and cerebellum as well as regulate locomotion. During the K99 phase, this project will complete the analysis of mutant brain anatomy. In addition, all mutants will be tested for behavioral abnormalities, including motor behaviors associated with schizophrenia, such as defective prepulse inhibition (Aim 1). In parallel, the developmental roles of ZNF536 will be studied to test the hypothesis that this transcription factor is responsible for the development of GABAergic neurons, and that its loss results in the de-inhibition of downstream circuits. To define the molecular mechanisms by which ZNF536 exerts its effects, ZNF536 target genes will be isolated (Aim 2). Similar in-depth characterization of other interesting genes will be undertaken in the R00 phase to discover additional pathways regulated by schizophrenia-associated genes. Understanding the molecular, cellular, developmental and behavioral processes regulated by schizophrenia- associated genes will provide the foundation to understand the causes of schizophrenia and develop new diagnostics and therapies.

项目总结/摘要 该项目的目标是研究精神分裂症相关基因的功能，使用斑马鱼作为 模型系统大规模的全基因组关联研究已经开始揭示许多候选基因。 与精神分裂症有关的基因然而，目前还不清楚这些基因是如何发挥作用的，以及它们是如何影响基因表达的。 潜在的分子、细胞、发育和行为过程在疾病中被破坏。最近 斑马鱼的技术突破-靶向基因组编辑，全脑活动成像，脑图谱 登记，行为分析-结合研究大量动物的容易性， 分析精神疾病基因的理想系统。初步研究导致了斑马鱼的诞生 96个精神分裂症相关基因的突变体。对其中59个突变体进行表征，以改变大脑 解剖学和活性揭示了27个具有表型异常的突变体。特别地，ZNF 536，a 精神分裂症相关转录因子，被发现参与GABA能的发展， 抑制性神经元在前脑和小脑以及调节运动。在K99阶段， 该项目将完成对突变大脑解剖的分析。此外，所有的突变体都将接受行为测试， 异常，包括与精神分裂症相关的运动行为，如前脉冲抑制缺陷 (Aim 1）。与此同时，ZNF 536的发育作用将被研究，以检验这一假设， 转录因子负责GABA能神经元的发育，其缺失导致GABA能神经元的发育异常。 解除下游电路的抑制。为了确定ZNF 536发挥作用的分子机制， 将分离ZNF 536靶基因（目的2）。类似的深入表征其他有趣的基因将 在R 00阶段进行，以发现精神分裂症相关基因调控的其他途径。 了解精神分裂症调节的分子，细胞，发育和行为过程- 相关基因将为理解精神分裂症的病因和开发新的 诊断和治疗。