Dissecting functional roles of schizophrenia risk gene ZNF804a in neural development

 描述（由申请人提供）：精神分裂症（SZ）和双相情感障碍（BP）等精神疾病是全球未满足医疗需求的毁灭性脑部疾病。在过去的两年中，全基因组相关研究（GWAS）已经确定了100多个强大的和可复制的风险位点，这可能为SZ的潜在生物学基础提供新的方面，并作为精神疾病的新药物靶点。然而，包括ZNF 804 a在内的许多新发现的神经系统风险基因的分子功能完全未知。因此，迫切需要阐明ZNF 804 a和其他风险基因的致病等位基因影响的潜在分子过程。缺乏这样的理解，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得到实质性改善。长期目标是阐明SZ风险的分子机制，并开发新的有效的治疗SZ的治疗干预策略。因此，本申请的目的是结合子宫内小鼠模型和体外人诱导性多能干细胞（iPSC）模型进一步研究ZNF 804 a在神经元发育中的作用。核心假设是ZNF 804 a对神经元分化至关重要，疾病相关SNP改变ZNF 804 a基因表达，从而调节神经元分化和迁移。该项目的基本原理是，它的成功完成将提供一个强有力的概念性循证框架，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等基因iPSC克隆。该中心假设将通过两个特定目的进行测试：1）确定ZNF 804 a在体内神经元迁移和分化中的关键作用;以及2）使用新型同基因人类iPSC确定ZNF 804 a及其内含子疾病相关等位基因的功能。申请人认为，该研究方案是创新性的，因为体外iPSC和体内小鼠模型的组合将允许显著降低患者来源的iPSC系中的遗传异质性，并提高检测常见风险变体的生物学读数的灵敏度。这一贡献将是重要的，因为它是在纯遗传背景下测量非编码遗传风险变异对疾病相关表型的影响的第一步。人类iPSC模型可以作为未来化学筛选的平台，以鉴定可以纠正与SZ和其他发育障碍相关的某些表型的小分子。

 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.