A Phenotypical Brain Organoids for Neurodevelopmental Disorders

项目摘要/摘要 神经发育障碍(NDDS)的特征是大脑发育中断，临床上 它们会导致神经功能受损。NDDS约占儿科慢性疾病的25%，是无法治愈的 并导致终生残疾。分子研究提高了我们对NDDS的理解，但规模仍然很大 知识上的差距是存在的。传统的研究工具，如鼠标模型，往往不能充分地模拟 这些条件。从患者来源的IPSCs中提取的人脑有机体(HBOS)可以捕捉到许多特征 以及发育中的大脑中的生物事件。然而，我们仍然不知道人类NDD能做得多好 在HBOS中建模。在这里，我建议调查可观察到的基因-表型相关性的范围 HBOS来自独特的患者派生的包含750个独立线路的IPSC文库，以检验四个假设：1]NDD- 衍生的HBOS是潜在的临床脑病理的敏感和特异的检测器。2]NDD-派生 HBOS显示出细胞和分子特征，揭示了大脑发育受阻的各个阶段。3] 将组学方法应用于这些体外衍生的HBOS可以揭示其潜在的机制 扰乱了发展。4]基因与环境的交互作用可以在HBOS中进行询问。 该奖项的培训阶段在加州大学圣地亚哥分校格里森博士的实验室进行，概述了一项全面的计划 获得技术和专业技能，使我能够过渡到独立研究 位置。该项目的成功完成将为今后旨在 结合我在干细胞命运决定方面的专业知识，我对这些 转录、表观遗传和结构的特殊性导致神经发育的大脑障碍。

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are characterized by disrupted development of the brain, and clinically they lead to impaired neurological function. NDDs account for ~25% of chronic pediatric disease, are incurable and result in lifelong impairments. Molecular studies have improved our understanding of NDDs, but still large gaps in knowledge exist. Conventional research tools like the mouse model does not often adequately model these conditions. Human brain organoids (hBOs) from patient-derived iPSCs can capture many characteristics and biological events in the developing brain. However, we still do not know how well human NDDs can be modeled in hBOs. Here, I propose to investigate the range of genotype-phenotype correlations observable in hBOs from a unique patient derived iPSC library of 750 independent lines to test four hypotheses: 1] NDD- derived hBOs are both sensitive and specific detectors of the underlying clinical brain pathology. 2] NDD-derived hBOs show both cellular and molecular hallmarks revealing the stages of disrupted brain development. 3] Omics approaches applied to these in-vitro derived hBOs can reveal underlying mechanisms of disrupted development. 4] Gene-environment interactions can be interrogated in hBOs. The training phase of the award, conducted in Dr. Gleeson’s lab at UCSD, outlines a comprehensive plan for acquisition of technical and professional skills that will enable my transition to an independent research position. The successful completion of this project will provide a platform for future experiments aimed to combine my expertise in stem cell fate decision to gain a deeper understanding of how does these transcriptional, epigenetic and structural specificities contribute to neurodevelopmental brain disorders.