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

项目摘要/摘要 在过去的十年里，科学界见证了人类基因的加速发现 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)、双相情感障碍和重度抑郁症。全基因组关联研究和全外显子组 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东西 由于我们对基因功能的了解有限，对临床可操作生物学的基因发现一直受到阻碍 以及相关的疾病机制。该领域的一个瓶颈是，大多数生物特征都集中在 在很少的NPD基因上，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，人们往往一次研究一个基因，这阻碍了我们理解 疾病机制。我们提出了另一种策略：对NPD基因进行大规模、公正、平行的研究 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 精神病学和神经发育障碍风险基因-SSPsygene)。我们建议建立化验 和数据生成中心(ADGC)，用于建立诱导多能干细胞(IPSC)来源的神经元模型 NPD(MiNND)，在那里我们将实施和优化新的可扩展和系统的分析方法，以审问 多达200个NPD危险基因的分子和神经生物学功能。与SSPsygene合作 并利用我们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将产生功能损失(LoF)IPSC人类神经 模型，并进行NPD的高含量形态计量和单细胞转录(scRNA-seq)分析 10个等位基因。我们还将使用光学传感器以高通量的方式分析突触功能并携带 进行多模式PatchSeq分析和建模，以从scRNA-seq数据预测神经元特性。最后， 与SSPsygene联盟合作，我们将进行数据集成、管理和传播到 研究界和公众进行进一步的分析。我们的MiNND-ADGC将建立一个宝贵的资源和 综合知识库，将为未来疾病机制的研究提供肥沃的基础。这个 在多种遗传背景下研究选定的NPD风险基因的数据，包括未被研究的 非洲裔美国人IPSC系，将使对潜在的交叉无序和跨种群的强有力的推断成为可能 与NPD相关的生物学趋同和发散。

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.