High-throughput interrogation of autism risk genes: from molecules to behavior

自闭症风险基因的高通量询问:从分子到行为

基本信息

  • 批准号:
    10639807
  • 负责人:
  • 金额:
    $ 38.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Over 1,000 genes have been implicated in autism spectrum disorder (ASD) but only a handful have been confirmed as causing phenotypes related to ASD in animal models. Understanding if and how each gene contributes to ASD-related phenotypes singly or in combination is not feasible with rodent models, which require enormous time, expense, and labor to generate and characterize. We have previously leveraged the nematode C. elegans as a minimum in vivo animal model to quickly characterize genes related to human neurological conditions. ------ C. elegans displays phenotypes with relevance to ASD including social behaviors represented by how they tend to clump together in piles while eating. To quickly gain insight into whether 109 SFARI gene orthologs play a role in social behaviors in C. elegans, rather than study one mutant at a time, we studied a collection of genetically distinct wild-type strains isolated from around the world. Each strain carries a distinct combination of variants in these 109 ASD risk genes. We discovered that overall, the number and severity of mutations in ASD risk genes correlated with decreased social behaviors. Moreover, we found that mutations in certain ASD risk genes appear to cause social deficits, because we could boost social behaviors by replacing defective ASD risk genes with functional versions. We also found that mutations in orthologs of genes that cause increased social behavior in C. elegans have already been implicated in positively modifying social behavior in ASD and Williams syndrome. The central hypothesis is that C. elegans will be a rapid and inexpensive model organism to determine which combinations of mutations in this vast number of risk genes cause ASD-related defects. The overall goal is to determine which mutations and combinations of mutations in ASD risk genes cause ASD-relevant behaviors, and by what mechanisms. The rationale is that there is an urgent need to understand the in vivo consequences of mutations in genes implicated in autism. The central hypothesis will be tested with three specific aims: 1) Identify which and how natural variants in ASD risk genes causally contribute to decreasing social behaviors and sensory integration in C. elegans. 2) Test which and how variants in ASD risk genes positively modify social behaviors and sensory integration in C. elegans. 3) Determine the mechanism by which genetic variants of uncertain significance identified in ASD patients influence social and sensory integration behaviors and neurobiology of C. elegans. ------ The research proposed in this application is innovative because it uses a minimalist animal model to perform high-throughput in vivo causal functional analyses of ASD risk genes. The work is significant because it will allow researchers working with rodents and human patients to focus their efforts on the most promising ASD risk genes. The results will empower families to understand how patient-specific mutations in unstudied or under-studied ASD risk genes influence basic neurobiology. Ultimately, such knowledge has the potential to guide the development of future pharmacological and genetic treatments for the symptoms of ASD.
项目概要 超过 1,000 个基因与自闭症谱系障碍 (ASD) 有关,但只有少数基因被证实 被证实在动物模型中引起与 ASD 相关的表型。了解每个基因是否以及如何 单独或组合地导致 ASD 相关表型对于啮齿动物模型来说是不可行的,这 需要大量的时间、费用和劳动力来生成和表征。我们之前已经利用了 线虫秀丽隐杆线虫作为最小体内动物模型,可快速表征与人类相关的基因 神经系统疾病。 ------ 线虫表现出与 ASD 相关的表型,包括社交行为 以它们在进食时倾向于聚集成堆为代表。快速了解是否 109 SFARI 基因直向同源物在秀丽隐杆线虫的社会行为中发挥作用,我们不是一次研究一种突变体,而是 研究了从世界各地分离出的一系列遗传独特的野生型菌株。每个菌株都携带一个 这 109 个 ASD 风险基因中不同的变异组合。我们发现,总体而言,数量和 自闭症谱系障碍(ASD)风险基因突变的严重程度与社会行为减少相关。此外,我们发现 某些 ASD 风险基因的突变似乎会导致社交缺陷,因为我们可以促进社交行为 通过用功能版本替换有缺陷的 ASD 风险基因。我们还发现直系同源物的突变 导致秀丽隐杆线虫社会行为增加的基因已经被认为与积极改变有关 自闭症谱系障碍和威廉姆斯综合症的社会行为。中心假设是秀丽隐杆线虫将是一种快速且 廉价的模型生物体来确定大量风险基因中的突变组合 导致 ASD 相关缺陷。总体目标是确定哪些突变和突变组合 自闭症谱系障碍 (ASD) 风险基因会导致自闭症谱系障碍 (ASD) 相关行为,以及通过什么机制。理由是,有一个 迫切需要了解与自闭症有关的基因突变的体内后果。中央 假设将通过三个具体目标进行检验:1)确定自闭症谱系障碍(ASD)风险基因的自然变异以及如何自然变异 导致线虫社会行为和感觉统合下降。 2) 测试哪个和 自闭症谱系障碍 (ASD) 风险基因的变异如何积极改变线虫的社会行为和感觉统合。 3) 确定自闭症谱系障碍(ASD)患者中确定意义不确定的遗传变异的机制 影响线虫的社会和感觉统合行为以及神经生物学。 ------ 研究 该应用中提出的方法具有创新性,因为它使用简约的动物模型来执行高通量 ASD 风险基因的体内因果功能分析。这项工作意义重大,因为它将使研究人员 与啮齿动物和人类患者合作,将精力集中在最有希望的自闭症谱系障碍风险基因上。这 结果将使家庭能够了解未经研究或研究不足的 ASD 患者特异性突变是如何发生的 风险基因影响基础神经生物学。最终,这些知识有可能指导 开发针对自闭症谱系障碍症状的未来药物和基因治疗方法。

项目成果

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JONATHAN THOMAS PIERCE其他文献

JONATHAN THOMAS PIERCE的其他文献

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{{ truncateString('JONATHAN THOMAS PIERCE', 18)}}的其他基金

Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
  • 批准号:
    10651500
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
  • 批准号:
    10841755
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
  • 批准号:
    10432743
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
Synergistic patterned neurodegeneration by APP and APOE4
APP 和 APOE4 的协同模式神经变性
  • 批准号:
    9414391
  • 财政年份:
    2017
  • 资助金额:
    $ 38.98万
  • 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
  • 批准号:
    8291979
  • 财政年份:
    2011
  • 资助金额:
    $ 38.98万
  • 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
  • 批准号:
    8478221
  • 财政年份:
    2011
  • 资助金额:
    $ 38.98万
  • 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
  • 批准号:
    8162634
  • 财政年份:
    2011
  • 资助金额:
    $ 38.98万
  • 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
  • 批准号:
    8846149
  • 财政年份:
    2011
  • 资助金额:
    $ 38.98万
  • 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
  • 批准号:
    8664453
  • 财政年份:
    2011
  • 资助金额:
    $ 38.98万
  • 项目类别:
Adaptive tissue permeability to alcohol in C. elegans
线虫对酒精的适应性组织渗透性
  • 批准号:
    8064549
  • 财政年份:
    2010
  • 资助金额:
    $ 38.98万
  • 项目类别:

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