Dissecting functional roles of schizophrenia risk gene ZNF804a in neural development

剖析精神分裂症风险基因 ZNF804a 在神经发育中的功能作用

基本信息

批准号：
9302529
负责人：
Yingwei Mao
金额：
$ 18.33万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302529
关键词：
Affect Alleles Biological Bipolar Disorder Brain Brain Diseases CRISPR/Cas technology Cell Adhesion Cell Line Cell model Chemicals Clone Cells Data Development Disease Embryo Environmental Risk Factor Functional disorder Future Gene Expression Genes Genetic Genetic Heterogeneity Genetic Risk Genome Genomics Genotype Goals Human In Vitro Individual Intervention Introns Knock-in Knock-out Measures Medical Mental disorders Molecular Mus National Heart, Lung, and Blood Institute Nervous system structure Neurodevelopmental Disorder Neuronal Differentiation Neurons Neuropsychology Pathogenicity Patients Phenotype Pluripotent Stem Cells Population Process Public Health Publishing Reporting Research Research Proposals Risk Role Schizophrenia Techniques Technology Testing Treatment Efficacy Variant base developmental disease drug development drug use screening evidence base expectation genetic element genetic predictors genetic variant genome editing genome-wide genomic variation improved in utero in vitro Model in vivo induced pluripotent stem cell innovation insight migration mouse model neocortical neurodevelopment neuroimaging neuron development new therapeutic target novel novel therapeutic intervention public health relevance risk variant small molecule treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Mental illnesses like schizophrenia (SZ) and bipolar disease (BP) are devastating brain disorders with global unmet medical needs. Significant accomplishments have identified over a hundred robust and replicable risk loci from genome-wide associated studies (GWAS) during last two years, which may provide novel aspects of the underlying biological basis of SZ and serve as new drug targets for psychiatric disorders. However, molecular functions of many newly-identified risk genes in the nervous system, including ZNF804a, are completely unknown. Thus, there is a critical need to elucidate the underlying molecular processes affected by pathogenic alleles of ZNF804a and other risk genes. Lack of such understanding, treatment options for psychiatric patients carrying similar risk alleles are unlikely to improve substantially. The long-term goal is to elucidate molecular mechanisms that underlie the risks for SZ and to develop novel and effective therapeutic intervention strategies for the treatment of SZ. The objective of this application, therefore, is t further investigate the role of ZNF804a in neuronal development combining both in utero mouse model and in vitro human inducible pluripotent stem cell (iPSC) model. The central hypothesis is that ZNF804a is vital for neuronal differentiation and the disease-associated SNP alters ZNF804a gene expression thereby regulates neuronal differentiation and migration. The rationale for this project is that its successful completion would provide a strong conceptual evidence-based frame-work to study many other noncoding genetic variants associated with SZ and to establish isogenic iPSC clones for future drug development. This central hypothesis will be tested by two Specific Aims: 1) Determine the critical role of ZNF804a in neuronal migration and differentiation in vivo; and 2) Determine the function of ZNF804a and its intronic disease-associated allele using novel isogenic human iPSCs. The research proposal is innovative, in applicant's opinion, because the combination of in vitro iPSC and in vivo mouse models will allow to significantly reduce the genetic heterogeneity in patient-derived iPSC lines and enhance the sensitivity to detect the biological readout for common risk variants. This contribution will be significant because it is the first step to measure the effect of noncoding genetic risk variant on disease-associated phenotypes in a pure genetic background. The human iPSC model may serve as a platform for the future chemical screen to identify small molecules that can correct certain phenotypes associated with SZ and other developmental disorders.

描述（由适用提供）：精神分裂症（SZ）和躁郁症（BP）等精神疾病是具有全球未满足医疗需求的毁灭性脑部疾病。在过去的两年中，来自全基因组相关研究（GWAS）的一百多个健壮且可复制的风险基因座的重大成就可以提供SZ基本生物学基础的新方面，并作为精神疾病的新药物目标。但是，包括ZnF804a在内的神经系统中许多新识别的风险基因的分子功能是完全未知的。这是迫切需要阐明受Znf804a和其他风险基因的致病等位基因影响的基本分子过程。缺乏这种理解，携带类似风险等位基因的精神病患者的治疗选择不太可能大幅改善。长期的目标是阐明SZ风险的基础，并制定新颖有效的治疗干预策略来治疗SZ。因此，该应用的目的是进一步研究ZnF804a在肠道神经元发展中的作用，在子宫小鼠模型和体外人类诱导的多能干细胞（IPSC）模型中都结合了ZnF804a。中心假设是ZNF804A对于神经元分化至关重要，与疾病相关的SNP改变了Znf804a基因表达，从而调节神经元分化和迁移。该项目的理由是，其成功完成将提供一个强大的概念性证据框架，以研究与SZ相关的许多其他非编码遗传变异，并为未来的药物开发建立同基因IPSC克隆。该中心假设将通过两个具体目的来检验：1）确定Znf804a在体内神经元迁移和分化中的关键作用； 2）确定Znf804a及其内含子疾病相关的等位基因的功能，使用新型的同源人IPSC。在应用程序中，该研究建议具有创新性，因为体外IPSC和体内小鼠模型的组合将使患者衍生的IPSC系列中的遗传异质性显着降低，并增强灵敏度以检测生物学读数的常见风险变化。这项贡献将是重要的，因为它是衡量非编码遗传风险变异对纯遗传背景中与疾病相关表型的影响的第一步。人IPSC模型可以作为未来化学筛选的平台，以识别可以纠正与SZ和其他发育障碍相关的某些表型的小分子。