Functional analysis of autism risk genes during neural development using single cell seq

使用单细胞测序对神经发育过程中自闭症风险基因进行功能分析

基本信息

批准号：
10334483
负责人：
Antonio J Giraldez
金额：
$ 56.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334483
关键词：
ASH1L gene Address Affect Automobile Driving Brain CNTNAP1 gene Cell Culture Techniques Cell physiology Cells Chromatin Chromatin Remodeling Factor Clustered Regularly Interspaced Short Palindromic Repeats Code Complex Computing Methodologies Development Disease Etiology Exhibits Gene Expression Generations Genes Genetic Genetic Models Genetic Transcription Genomics Glutamates Goals Human Individual Knowledge Life Maps Methods Modeling Modification Molecular Mutation Neurons Neurophysiology - biologic function Organ Organoids Pathway interactions Regulator Genes Research Resolution Role Shapes Specific qualifier value Synaptic plasticity System Testing Work Zebrafish autism spectrum disorder brain cell cell type combinatorial disorder risk estrogenic experimental study gene regulatory network genome-wide in vivo innovation insight loss of function loss of function mutation mutant nerve stem cell neurodevelopment neurogenesis neuromechanism novel programs protein protein interaction relating to nervous system response risk variant single cell sequencing single-cell RNA sequencing transcription factor transcriptomics vertebrate embryos

项目摘要

The brain represents a complex organ with a myriad of functionally diverse cell types. Autism spectrum disorder (ASD) is thought to alter the combinatorial transcriptional and post-transcriptional code responsible for specifying and maintaining different cell functions in the vertebrate brain. The proposed studies will test the central hypothesis that chromatin/transcriptional regulators identified as ASD risk genes act as developmental switches during early neurodevelopment, altering the gene expression network and subsequent cell function. In this proposal we combine single cell sequencing, with genetic, genomic and computational approaches in zebrafish and embryoid bodies to i) characterize the role of ASD-risk genes in healthy neural gene regulatory networks (Aim 1); 2) Interrogate the effects of ASD loss-of-function (LOF) mutations in different neural lineages (Aim 2). Cell types and developmental lineages within the brain that are more significantly affected by each candidate ASD risk gene will be identified using zebrafish and human cell–derived organoids. The experiments outlined in this proposal have the ultimate goal of identifying how ADS risk genes affect neural gene expression and cell function during vertebrate development.

大脑是一个复杂的器官，具有多种功能自闭症谱系障碍（ASD）被认为会改变组合。转录和转录后代码负责指定和维持脊椎动物大脑中的不同细胞功能。将检验染色质/转录调节因子确定的中心假设因为自闭症谱系障碍 (ASD) 风险基因在早期起着发育开关的作用神经发育，改变基因表达网络和后续细胞功能。在此提案中，我们将单细胞测序与遗传、基因组测序相结合以及斑马鱼和拟胚体的计算方法 i) 描述 ASD 风险基因在健康神经基因调节中的作用网络（目标 1）；2）询问 ASD 功能丧失 (LOF) 的影响不同神经谱系的突变（目标 2）。大脑中受每个候选者影响更大的谱系 ASD 风险基因将利用斑马鱼和人类细胞来源进行鉴定类器官。本提案中概述的实验的最终目标是确定 ADS 风险基因如何影响神经基因表达和细胞功能在脊椎动物发育过程中。