A Phenotypical Brain Organoids for Neurodevelopmental Disorders

项目总结/摘要 神经发育障碍（NDD）的特征在于大脑发育中断，并且临床上 会导致神经功能受损NDD占慢性儿科疾病的约25%，无法治愈 并导致终身残疾。分子研究提高了我们对NDD的理解，但仍然很大。 存在知识差距。传统的研究工具，如小鼠模型，往往不能充分模拟 了以下条件来自患者来源的iPSC的人脑类器官（hBO）可以捕获许多特征 和大脑发育中的生物学事件。然而，我们仍然不知道人类NDD的效果如何 在hBO中建模。在这里，我建议调查的范围内的基因型-表型相关性观察， 来自750个独立系的独特患者来源的iPSC文库的hBO以测试四个假设：1] NDD- 衍生的hBO是潜在的临床脑病理学的敏感和特异的检测器。2]NDD衍生 hBO显示出细胞和分子标志，揭示了大脑发育中断的阶段。三、 应用于这些体外衍生的hBO的组学方法可以揭示其潜在的机制。 中断发展。4]基因-环境相互作用可以在hBO中进行询问。 该奖项的培训阶段，在格里森博士在加州大学圣地亚哥分校的实验室进行，概述了一个全面的计划， 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的实验提供一个平台， 联合收割机结合我在干细胞命运决定方面的专业知识，更深入地了解这些 转录、表观遗传和结构特异性导致神经发育脑障碍。

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.