Uncovering the Role of TRIO in Synaptic Function and Autism Spectrum Disorder

揭示 TRIO 在突触功能和自闭症谱系障碍中的作用

• 批准号: 10622528
• 负责人: Bruce Herring
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622528
• 关键词: Actins; Address; Age of Onset; Area; Behavior; Biochemical; Brain; Clupeidae; Communication; Computer Models; Data; Development; Dimensions; Disease; Electrophysiology (science); Engineering; Functional disorder; Genetic; Glutamates; Goals; Guanine Nucleotide Exchange Factors; Imaging Techniques; Impairment; Individual; Influentials; Investigation; Knock-in Mouse; Knowledge; Lifestyle-related condition; Link; Mediating; Mental disorders; Mission; Molecular Abnormality; Monomeric GTP-Binding Proteins; Morphology; Mus; Mutation; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Neurologic; Neurologic Deficit; Neurons; Pathologic; Pathway interactions; Phenotype; Play; Polymers; Principal Investigator; Proteins; Proteomics; Psyche structure; Public Health; Regulation; Regulatory Pathway; Research; Role; Sensory; Signal Transduction; Spectrin; Structure; Symptoms; Synapses; Synaptic Transmission; TRIO gene; Techniques; Time; Work; autism spectrum disorder; autistic; behavior test; behavioral phenotyping; de novo mutation; genetic regulatory protein; genome-wide; innovation; interest; mutant; neurotransmission; novel; novel therapeutic intervention; polymerization; postnatal development; postsynaptic; programs; protein function; risk variant; somatosensory; stem; superresolution imaging; synaptic function; synaptogenesis; tool

Program Director/Principal Investigator (Last, First, Middle): Herring, Bruce, E. PROJECT SUMMARY Autism Spectrum Disorder (ASD) is a leading cause of mental impairment for which there is no known cure. Mounting evidence points to a convergence on altered actin-mediated regulation of postsynaptic glutamatergic synaptic function as a basis for ASD. We have recently identified an unprecedented clustering of ASD-related mutations in the GEF1 domain of the synaptic actin regulatory protein, Trio, that results in a strong genome-wide statistical association of the TRIO gene with ASD. The long-term goal of our research is to identify core synaptic regulatory machinery onto which numerous ASD causing factors converge. Identification of synaptic “convergence points” of ASD-risk genes will help simplify the genetic landscape of this disorder and thus, aid in the development of new strategies to treat individuals with a diverse array of ASD-causing factors. Our central hypothesis is that ASD mutations in Trio disrupt a multitude of synaptic regulatory pathways, and that disruption of these pathways results in glutamatergic synapse dysfunction that contributes to the development of ASD- related behavioral phenotypes. Guided by strong preliminary data we will pursue this hypothesis in three specific aims. In Aim 1, we will combine proteomic, biochemical, electrophysiological, and super-resolution imaging techniques to identify novel synaptic regulatory mechanisms involving Trio. In Aim 2, we will combine these same approaches with computational modeling to reveal Trio-related synaptic regulatory mechanisms disrupted by Autism-related mutations and provide a comprehensive picture of the synaptic disruption that results from Autism-specific Trio dysfunction. And, for Aim 3, we have engineered a conditional knock-in mouse that allows CRE-dependent expression of an ASD-related mutant form of Trio. Using this new and powerful genetic tool, we will conduct a battery of behavioral tests to assess the impact of ASD-related Trio mutations on mammalian behavior. Growing evidence now suggests that neurological sensory processing deficits underlie the development of many common ASD-related behavioral phenotypes. Because of this, we propose the use of state-of-the-art techniques that allow careful examination of somatosensory processing in these mice. The present proposal is innovative because it assembles a team of collaborators with diverse areas of expertise and deploys new and powerful genetic tools that will allow a multi-dimensional approach to understanding how disruption of synaptic function leads to ASD. The proposal is significant because it stands to identify an important synaptic signaling hub that links numerous synaptic proteins previously implicated in ASD and will vertically advance our understanding of ASD from synapse to circuit to behavior. This proposal squarely meets the mission objectives of the NINDS given its focus on how synaptic dysfunction ultimately leads to key neurological deficits that likely underlie many core behavioral phenotypes associated with ASD. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Continuation Format Page

计划主任/首席研究员（最后，第一，中间）：鲱鱼，布鲁斯，E。 项目摘要 自闭症谱系障碍（ASD）是无法治愈的精神障碍的主要原因。 安装证据表明，肌动蛋白介导的突触后谷氨酸能的调节改变了。 突触功能作为ASD的基础。我们最近确定了与ASD相关的前所未有的聚类 突触肌动蛋白调节蛋白的GEF1结构域中的突变三重奏，导致全基因组强大 三人基因与ASD的统计关联。我们研究的长期目标是确定核心突触 许多ASD导致因素收敛的调节机制。突触的识别 ASD风险基因的“收敛点”将有助于简化这种疾病的遗传景观，从而有助于帮助 制定新策略，以治疗各种各样的ASD引起的因素。我们的中心 假设三重奏中的ASD突变破坏了多种突触调节途径，并且破坏了 在这些途径中，导致谷氨酸能突触功能障碍有助于ASD-的发展 相关的行为表型。在强大的初步数据的指导下，我们将在三个特定的特定方面提出这一假设 目标。在AIM 1中，我们将结合蛋白质组学，生化，电生理和超分辨率成像 识别涉及三重奏的新型突触调节机制的技术。在AIM 2中，我们将将这些结合在一起 使用计算建模的方法，以揭示三重奏相关的突触调节机制被破坏 与自闭症相关的突变，并提供了由 自闭症特异性三重奏功能障碍。而且，对于AIM 3，我们设计了一种有条件的敲入鼠标，该鼠标允许 三重奏的ASD相关突变体形式的CRE依赖性表达。使用这种新的强大遗传工具，我们 将进行一系列行为测试，以评估与ASD相关的三人突变对哺乳动物的影响 行为。现在越来越多的证据表明，神经系统感觉处理缺陷是 发展许多与ASD相关的行为表型的发展。因此，我们建议使用 可以仔细检查这些小鼠的体感处理的最新技术。 目前的提案具有创新性，因为它组建了一个合作者团队，该团队拥有专业知识和 部署新的强大遗传工具，将允许多维方法来理解如何 突触功能的破坏导致ASD。该提议很重要，因为它是确定重要的 突触信号集线器连接了先前在ASD中实现的许多合成蛋白，并将垂直上 使我们对ASD的理解从突触到电路再到行为。该提议完全符合任务 Ninds的目标鉴于其关注突触功能障碍如何最终导致关键神经功能不全 与ASD相关的许多核心行为表型的基础。 OMB编号0925-0001/0002（修订版01/18通过03/31/2020批准）延续格式页面