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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：
10526025
负责人：
Lu Wang
金额：
$ 10.56万
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/10526025
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 Disease Disease model Environment Epigenetic Process Epilepsy Evaluation Event Feedback Fingerprint Foundations Future Gene Mutation Genes Genetic Genetic Transcription Genotype Goals Human Hypoxia Impairment In Vitro Individual Intellectual functioning disability Knowledge Lead 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 base causal variant cell type clinical diagnosis clinically relevant detector drug development experimental study gene environment interaction improved induced pluripotent stem cell mouse model novel optical imaging promoter protein expression relating to nervous system 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.

项目总结/文摘