Functional Analysis of Schizophrenia-Associated Genes

项目摘要/摘要 该项目的目标是以斑马鱼为研究对象，研究精神分裂症相关基因的功能。 模型系统。大规模的全基因组关联研究已经开始发现许多候选 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，以及它们是如何对 潜在的分子、细胞、发育和行为过程在这种疾病中被破坏。近期 斑马鱼靶向基因组编辑、全脑活动成像、脑图谱的技术突破 登记，行为分析--再加上研究大量动物的简便性，使其成为一种 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。59个脑改变突变体的特征分析 解剖和活性已经发现了27个具有表型异常的突变。特别是，ZNF536，一种 精神分裂症相关转录因子被发现参与GABA能 前脑和小脑中的抑制神经元以及调节运动。在K99阶段，这是 该项目将完成对突变脑部解剖结构的分析。此外，所有变种人都将接受行为测试 异常，包括与精神分裂症有关的运动行为，如脉冲前抑制缺陷 (目标1)。同时，将研究ZNF536的发育作用，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 解除下游电路的抑制。为了确定ZNF536发挥作用的分子机制， 将分离ZNF536靶基因(目标2)。对其他有趣基因的类似深入描述将 在R00阶段进行，以发现更多受精神分裂症相关基因调控的途径。 了解精神分裂症调节的分子、细胞、发育和行为过程- 相关基因将为了解精神分裂症的病因和开发新的 诊断和治疗。

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.