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：
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
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

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

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.

项目摘要超过1,000个基因与自闭症谱系障碍有关（ASD），但只有少数几个被证实是引起与动物模型中ASD相关的表型。了解每个基因是否以及如何啮齿动物模型可单独或组合有助于ASD相关的表型，这是不可行的需要巨大的时间，费用和劳动才能产生和表征。我们以前利用了线虫C.秀丽隐杆线虫是最低的体内动物模型，以快速表征与人有关的基因神经条件。 ------秀丽隐杆线虫显示与ASD相关的表型，包括社交行为以他们在进食时如何将堆成堆成堆积的代表。迅速了解是否109 Sfari基因直系同源物在秀丽隐杆线虫的社会行为中起作用，而不是一次研究一个突变体，我们研究了与世界各地隔离的一系列遗传上不同的野生型菌株。每个菌株都带有这109个ASD风险基因中变体的独特组合。我们发现总体上，数量和 ASD风险基因突变的严重程度与社会行为减少相关。而且，我们发现某些ASD风险基因的突变似乎会导致社会缺陷，因为我们可以促进社会行为通过用功能版本代替有缺陷的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中社会行为增加的基因已经与积极修改有关 ASD和Williams综合征的社会行为。中心假设是秀丽隐杆线虫将是一个迅速而又廉价的模型生物体，以确定大量风险基因中突变的哪些组合导致与ASD相关的缺陷。总体目标是确定突变的突变和组合 ASD风险基因引起与ASD相关的行为，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中突变的体内后果。中央假设将以三个特定的目的进行检验：1）确定ASD风险基因的自然变异因果关系有助于减少秀丽隐杆线虫中的社会行为和感觉融合。 2）测试哪个和 ASD风险基因中的变体如何积极地修改秀丽隐杆线虫中的社会行为和感觉整合。 3）确定ASD患者中具有不确定意义的遗传变异的机制影响秀丽隐杆线虫的社会和感觉整合行为和神经生物学。 ------研究在此应用中提出的是创新的，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。这项工作很重要，因为它将允许研究人员与啮齿动物和人类患者一起工作，将精力集中在最有前途的ASD风险基因上。这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本的神经生物学。最终，这种知识有可能指导开发ASD症状的未来药理和遗传处理。