Assay and Data Generation Center (ADGC) for the Model of iPSC-derived Neurons for NPD (MiNND)

项目总结/摘要 在过去的十年里，科学界见证了加速的基因发现， 神经发育和精神障碍（NPD），如精神分裂症（SZ）、自闭症谱系障碍（ASD）、 (ASD)躁郁症和重度抑郁症。全基因组关联研究（GWAS）和全外显子组 测序（WES）已经确定了越来越多的NPD风险基因。然而，翻译这些令人兴奋的 由于我们对基因功能的了解有限， 相关疾病机制。该领域的一个瓶颈是，大多数生物学表征都集中在 很少的NPD基因，这些基因不一定被选择用于基于病理生理学的研究。 重要性此外，基因往往是一次研究一个，阻碍了我们理解的步伐， 疾病机制。我们提出了另一种策略：大规模，无偏，平行研究NPD基因 在疾病相关模型系统中，响应RFA-MH-22-111（可扩展和系统神经生物学 精神和神经发育障碍风险基因（SSPsyGene）。我们建议建立含量测定 和数据生成中心（ADGC）的诱导多能干细胞（iPSC）衍生的神经元模型， NPD（MiNND），在那里我们将实施和优化新的可扩展的和系统的测定，以询问 多达200个NPD风险基因的分子和神经生物学功能。与SSPsyGene合作 联盟和利用我们的团队在干细胞生物学，功能基因组学， 神经科学和功能分析，我们的MiNND-ADGC将产生功能丧失（LoF）的iPSC人类神经 模型，并进行NPD的高含量形态测定和单细胞转录组学（scRNA-seq）分析 LoF等位基因。我们还将使用光学传感器以高通量的方式测定突触功能，并进行 通过多模式PatchSeq分析和建模，从scRNA-seq数据中预测神经元特性。最后， 与SSPsyGene联盟合作，我们将进行数据集成，管理和传播， 研究社区和公众进行进一步分析。我们的MiNND-ADGC将建立一个宝贵的资源， 综合知识库，将为未来的疾病机制研究提供肥沃的基础。的 研究选定的NPD风险基因在多种遗传背景下的数据，包括研究不足的 非洲裔美国人iPSC系，将能够对潜在的交叉疾病和交叉人群进行强有力的推断。 与新产品开发相关的生物学趋同和趋异。

Project Summary/Abstract In the past decade, the scientific community has witnessed accelerated genetic discoveries for neurodevelopmental and psychiatric disorders (NPD) such as schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder, and major depression. Genome-wide association studies (GWAS) and whole-exome sequencing (WES) have identified a mounting number of NPD risk genes. However, translating these exciting genetic discoveries into clinically actionable biology has been impeded by our limited knowledge of gene function and related disease mechanisms. A bottleneck in the field is that most biological characterization has focused on very few NPD genes, which have not necessarily been selected for study based on pathophysiological importance. Furthermore, genes are often studied one at a time, hindering the pace of our understanding of disease mechanisms. We propose an alternative strategy: large-scale, unbiased, parallel study of NPD genes in disease-relevant model systems, in response to the RFA-MH-22-111 (Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes-SSPsyGene). We propose to establish the Assay and Data Generation Center (ADGC) for the Model of induced pluripotent stem cell (iPSC)-derived Neurons for NPD (MiNND), where we will implement and optimize novel scalable and systematic assays for interrogating the molecular and neurobiological functions of up to 200 NPD risk genes. Teaming up with the SSPsyGene Consortium and leveraging our team’s respective expertise in stem cell biology, functional genomics, neuroscience, and functional analysis, our MiNND-ADGC will generate loss-of-function (LoF) iPSC human neural models, and perform high-content morphometric and single-cell transcriptomic (scRNA-seq) analyses of NPD LoF alleles. We will also assay synaptic functions using optical sensors in a high-throughput fashion and carry out multimodal PatchSeq analyses and modeling to predict neuronal properties from scRNA-seq data. Finally, working with the SSPsyGene Consortium, we will conduct data integration, curation, and dissemination to the research community and public for further analysis. Our MiNND-ADGC will build a valuable resource and integrated knowledge base that will provide a fertile foundation for future studies of disease mechanisms. The data from studying the selected NPD risk genes on multiple genetic backgrounds, including the understudied African American iPSC lines, will enable robust inferences of potential cross-disorder and cross-population biological convergence and divergence relevant to NPD.