A Phenotypical Brain Organoids for Neurodevelopmental Disorders

治疗神经发育障碍的表型脑类器官

基本信息

批准号：
10676198
负责人：
Lu Wang
金额：
$ 10.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676198
关键词：
3-Dimensional ATAC-seq Affect Atlases Award Bar Codes Biological Biological Markers Brain Brain Diseases Brain Pathology Categories Cells Characteristics Childhood Chromatin Chronic Classification Clinical Collaborations Complex Coupled Data Defect Development Dimensions Disease Disease model Environment Epigenetic Process Epilepsy Evaluation Event Feedback Fingerprint Foundations Future Gene Combinations Gene Mutation Genetic Genetic Transcription Genotype Goals Human Hypoxia Impairment In Vitro Individual Intellectual functioning disability Knowledge Libraries Light Link Logistics Mali Maps Mentors Methods Microcephaly Microgyria Microscope Microscopy Modeling Molecular Morphology Mutation Nervous System Physiology Neurodevelopmental Disorder Neurons Organoids Outcome Measure Patients Persons Phase Phenotype Positioning Attribute Precision therapeutics Proteomics Reporter Research Resolution Sampling Seizures Solid Specificity Stress System Temperature Testing Three-Dimensional Imaging Time Training Virus Virus Diseases Work causal variant cell type clinical diagnosis clinically relevant data integration detector drug development experimental study gene environment interaction improved induced pluripotent stem cell mouse model neural novel optical imaging promoter protein expression skills small molecule stem cell fate tool

项目摘要

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.

项目概要/摘要神经发育障碍 (NDD) 的特点是大脑发育障碍，临床上它们会导致神经功能受损，约占慢性儿科疾病的 25%，并且是无法治愈的。分子研究提高了我们对 NDD 的理解，但仍然很大。传统的研究工具（例如小鼠模型）通常无法充分建模。来自患者的 iPSC 的人脑类器官 (hBO) 可以捕获许多特征。然而，我们仍然不知道人类 NDD 的效果如何。在这里，我建议研究可观察到的基因型-表型相关性的范围。 hBO 来自独特的患者衍生 iPSC 文库（包含 750 个独立细胞系），用于测试四种假设：1] NDD- 衍生的 hBO 是潜在临床脑病理学的敏感且特异的检测器 2] NDD 衍生的。 hBO 显示出细胞和分子特征，揭示了大脑发育中断的阶段 3]。应用于这些体外衍生的 hBO 的组学方法可以揭示潜在的机制 4] 可以在 hBO 中探究基因与环境的相互作用。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该项目的成功完成将为今后的实验提供一个平台。结合我在干细胞命运决定方面的专业知识，以更深入地了解这些转录、表观遗传和结构特异性会导致大脑神经发育障碍。