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

• 批准号: 10639807
• 负责人: JONATHAN THOMAS PIERCE
• 金额: $ 38.98万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10639807
• 关键词: ASD patient; Alleles; Animal Model; Behavior; Behavioral; Biology; Breeding; CRISPR/Cas technology; Caenorhabditis elegans; Cells; Certification; Classification; Collection; Cryopreservation; Databases; Defect; Development; Eating; Family; Foundations; Future; Gene Combinations; Gene Expression Profiling; Gene Transfer Techniques; Genes; Genetic; Goals; Human; Impairment; Knowledge; Linear Regressions; Molecular; Molecular Genetics; Morphology; Mutation; Nematoda; Neurobiology; Neurologic; Neurons; Orthologous Gene; Pathway interactions; Patients; Phenotype; Pilot Projects; Positioning Attribute; Research; Research Personnel; Risk; Rodent; Rodent Model; SYNGAP1; Sensory; Severities; Social Behavior; Social Change; Socialization; Stimulus; Structure; Synapses; Testing; Time; Transgenic Organisms; Variant; Williams Syndrome; Work; autism spectrum disorder; axon guidance; causal variant; empowerment; endophenotype; gene conservation; genetic variant; genome wide association study; high risk; in vivo; in vivo Model; innovation; insight; model organism; motor behavior; mutant; neural circuit; novel; overexpression; pharmacologic; response; risk variant; sensory integration; social; social deficits; social influence; social integration; symptom treatment; variant of unknown significance

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.

项目摘要 超过1，000个基因与自闭症谱系障碍（ASD）有关，但只有少数基因与自闭症谱系障碍（ASD）有关。 在动物模型中证实为引起与ASD相关的表型。了解每个基因 单独或组合地导致ASD相关表型对于啮齿动物模型是不可行的， 需要大量的时间、费用和劳动力来生成和表征。我们以前利用了 线虫C.线虫作为最小的体内动物模型，以快速表征人类相关基因 神经系统疾病- C.秀丽线虫表现出与ASD相关的表型，包括社会行为 表现为它们在进食时往往会聚集在一起。为了快速了解是否109 SFARI基因同源基因在C.与其一次研究一个突变体， 研究了一组从世界各地分离出来的基因上不同的野生型菌株。每种菌株都携带一个 这109个ASD风险基因中的变体的独特组合。我们发现，总的来说， ASD风险基因突变的严重程度与社交行为减少相关。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， 用功能性的基因替换有缺陷的ASD风险基因。我们还发现， 导致C.秀丽线虫已经被证实 ASD和威廉姆斯综合征中社会行为中心假设是C. elegans将是一个快速， 一种廉价的模式生物，以确定在这些大量的风险基因中， 导致ASD相关缺陷。总的目标是确定哪些突变和突变的组合， ASD风险基因导致ASD相关行为，以及通过什么机制理由是， 我们迫切需要了解与自闭症有关的基因突变的体内后果。中央 我们将通过三个具体目标来检验这一假设：1）确定ASD风险基因中哪些自然变异以及如何自然变异 导致C.优美的2)测试哪个和 ASD风险基因的变异如何积极地改变C.优美的第三章 确定在ASD患者中识别不确定意义的遗传变异的机制 影响C.优美的--研究 本申请中提出的方法是创新的，因为它使用了最低限度的动物模型来进行高通量的 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，将他们的努力集中在最有希望的ASD风险基因上。的 结果将使家庭能够了解未研究或研究不足的ASD中的患者特异性突变 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ASD症状的未来药理学和基因治疗方法。