High-throughput modeling of autism risk genes using zebrafish

使用斑马鱼进行自闭症风险基因的高通量建模

基本信息

  • 批准号:
    10478187
  • 负责人:
  • 金额:
    $ 75.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Autism spectrum disorder (ASD) is caused by both environmental and genetic factors, with the genetic contribution estimated at 60-80%. Dozens of genes that increase risk for ASD have been identified, most based on de novo mutations, but these mutations are predicted to account for only 15-20% of ASD cases. Thus, the majority of the genetic contribution to ASD is predicted to result from common and rare inherited variation, but few such genes have been identified. Recently, using whole genome sequencing, we reported genome wide evidence for >60 ASD risk genes, 26 of them novel for ASD, with signals derived from inherited and de novo protein truncating or missense mutations. The functions of most of these genes are unknown, so a crucial and necessary next step is to explore their impact on neurodevelopment and neuronal function using a model organism. The current pace of translating genetic risk factors into phenotypes, mechanisms and therapies is limited in part by inefficiencies with in vivo mammalian model systems, which makes them impractical for creating and behaviorally testing large numbers of mutant lines. Here, we leverage the zebrafish, which occupies a unique niche as a vertebrate model with features amenable to both in vivo screening and mechanistic understanding, including ex utero development, transparency, small size, rapid development, a conserved yet relatively simple vertebrate brain, behaviors relevant to ASD, and cost-effectiveness relative to mammalian models. While the zebrafish cannot recapitulate ASD and has limitations for modeling a human disorder, an emerging literature supports the notion that it is a useful model to study the functions of genes that contribute to ASD risk. Rather than assess ASD-risk genes one at a time, we will accelerate progress towards mechanistic understanding via high-throughput assays and analyses. In Specific Aim 1 we will generate null mutations in the zebrafish orthologs of 24 high confidence, novel, genome-wide significant ASD risk genes, and systematically test each mutant for neurodevelopmental, behavioral, neuronal network, and transcriptomic phenotypes. In Specific Aim 2, we will use transcriptomic analyses, at the whole brain and single cell levels, to integrate ASD risk genes into functional networks, and test for convergence across genes and species, including ASD post mortem brain. We will also test for functional associations among behavioral phenotypes that are often co-morbid in ASD, such as disrupted sleep and social behavioral deficits. In Specific Aim 3 we will perform mechanistic studies to understand how mutation of specific ASD-risk genes leads to phenotypes. This project will efficiently and cost-effectively create and characterize vertebrate animal models for a large number of novel ASD risk genes. These animal models will be a valuable resource for the community, particularly for large-scale in vivo drug screens to identify new therapies for ASD.
自闭症谱系障碍(ASD)是由环境和遗传因素共同引起的,具有遗传性

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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DANIEL H GESCHWIND其他文献

DANIEL H GESCHWIND的其他文献

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{{ truncateString('DANIEL H GESCHWIND', 18)}}的其他基金

Project 2: Impact of H1/H2 haplotypes on cellular disease-associated phenotypes driven by FTD-causing MAPT mutations
项目 2:H1/H2 单倍型对 FTD 引起的 MAPT 突变驱动的细胞疾病相关表型的影响
  • 批准号:
    10834336
  • 财政年份:
    2023
  • 资助金额:
    $ 75.66万
  • 项目类别:
UCLA High-Throughput Neuropsychiatric Disorder Phenotyping Center (UCLA HT-NPC)
加州大学洛杉矶分校高通量神经精神疾病表型中心 (UCLA HT-NPC)
  • 批准号:
    10643541
  • 财政年份:
    2023
  • 资助金额:
    $ 75.66万
  • 项目类别:
Uncovering the Genetic Mechanisms of the Chromosome 17q21.31 Tau Haplotype on Neurodegeneration Risk in FTD and PSP
揭示染色体 17q21.31 Tau 单倍型对 FTD 和 PSP 神经变性风险的遗传机制
  • 批准号:
    10789246
  • 财政年份:
    2023
  • 资助金额:
    $ 75.66万
  • 项目类别:
Project 2: Impact of H1/H2 haplotypes on cellular disease-associated phenotypes driven by FTD-causing MAPT mutations
项目 2:H1/H2 单倍型对 FTD 引起的 MAPT 突变驱动的细胞疾病相关表型的影响
  • 批准号:
    10295518
  • 财政年份:
    2021
  • 资助金额:
    $ 75.66万
  • 项目类别:
Uncovering the genetic mechanisms of the Chromosome 17q21.31 Tau haplotype on neurodegeneration risk in FTD and PSP
揭示染色体 17q21.31 Tau 单倍型对 FTD 和 PSP 神经变性风险的遗传机制
  • 批准号:
    10902613
  • 财政年份:
    2021
  • 资助金额:
    $ 75.66万
  • 项目类别:
Uncovering the genetic mechanisms of the Chromosome 17q21.31 Tau haplotype on neurodegeneration risk in FTD and PSP
揭示染色体 17q21.31 Tau 单倍型对 FTD 和 PSP 神经变性风险的遗传机制
  • 批准号:
    10295512
  • 财政年份:
    2021
  • 资助金额:
    $ 75.66万
  • 项目类别:
High-throughput Modeling of Autism Risk Genes using Zebrafish - DIVERSITY SUPPLEMENT
使用斑马鱼对自闭症风险基因进行高通量建模 - 多样性补充
  • 批准号:
    10818861
  • 财政年份:
    2020
  • 资助金额:
    $ 75.66万
  • 项目类别:
High-throughput modeling of autism risk genes using zebrafish
使用斑马鱼进行自闭症风险基因的高通量建模
  • 批准号:
    10121604
  • 财政年份:
    2020
  • 资助金额:
    $ 75.66万
  • 项目类别:
High-throughput modeling of autism risk genes using zebrafish
使用斑马鱼进行自闭症风险基因的高通量建模
  • 批准号:
    10264069
  • 财政年份:
    2020
  • 资助金额:
    $ 75.66万
  • 项目类别:
Genetic Investigation of Minimally Verbal Children with ASD
患有自闭症谱系障碍(ASD)的最少语言儿童的基因调查
  • 批准号:
    10470956
  • 财政年份:
    2019
  • 资助金额:
    $ 75.66万
  • 项目类别:

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