An informatics approach to examine genetic and environmental regulation of the PI3K-AKT-mTOR pathway in autism spectrum disorder

一种信息学方法来检查自闭症谱系障碍中 PI3K-AKT-mTOR 通路的遗传和环境调节

• 批准号: 10225341
• 负责人: Kaleab Kidane Tessema
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225341
• 关键词: ASD patient; Acute; Address; Adult; Affect; Automobile Driving; Behavior; Behavior Therapy; Behavioral; Biological; Biological Assay; Biological Markers; Biological Process; Biological Response Modifier Therapy; Biology; Brain; CRISPR/Cas technology; California; Cells; Cerebrum; Child; Clinical; Comprehensive Cancer Center; Defect; Development; Doctor of Philosophy; Enrollment; Environmental Exposure; Environmental Risk Factor; Exposure to; FRAP1 gene; Family; Future; Gene Expression; Genetic; Genome engineering; Grooming; Growth; Health Care Costs; Heterozygote; Histology; Homeostasis; Human; Image; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Informatics; Intellectual and Developmental Disabilities Research Centers; Link; Los Angeles; Macrocephaly; Mediating; Mediator of activation protein; Medical; Mental Health; Molecular; Mus; Mutation; Neurites; Neurobiology; Neurons; Organoids; Outcome; PTEN gene; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Prevalence; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regenerative Medicine; Regulation; Research; Risk Factors; Scientist; Signal Transduction; Sirolimus; Social Interaction; Stem Cell Research; Structure; Synapses; Techniques; Therapeutic; Training; Training Programs; Universities; autism spectrum disorder; behavior influence; biopsychosocial; brain cell; brain overgrowth; cell type; cost; experience; gene environment interaction; in utero; individual patient; induced pluripotent stem cell; insight; interest; mTOR inhibition; motor behavior; mouse model; neurodevelopment; prevent; repetitive behavior; response; single-cell RNA sequencing; tool; transcriptomics; translational study

PROJECT SUMMARY Autism spectrum disorder (ASD) accounts for a large individual, familial, and societal burden. The lives of patients and their families are also significantly impacted, as the biopsychosocial effects generally impair functioning in multiple settings. Currently, treatment approaches focus on behavioral therapy since developing biological treatments has been challenging due to the variability in causative mechanisms and lack of reliable biomarkers. To address this challenge, it is crucial to uncover common pathogenic mechanisms underlying multiple ASD risk factors, as such understanding could eventually help develop therapeutic strategies for larger groups of patients. One candidate pathway that has been studied in a subset of ASD patients is the PI3K-AKT- mTOR pathway. Evidence suggests that this pathway can become dysregulated in response to both genetic and environmental influences, though the mechanistic link to ASD remains unclear. This proposal seeks to examine one environmental (exposure to maternal inflammation in utero) and one genetic (heterozygous mutations in PTEN) regulator of mTOR and probe neurobiological phenomena using state-of-the-art techniques. Specifically, the persistence and reversibility of abnormal repetitive behavior in adult mice exposed to maternal inflammation in utero will be assessed in the MIR mouse model developed in the Kornblum Lab, using single-cell informatics approaches to determine how mTOR acutely regulates neuronal activity and behavior. Further, possible developmental links to ASD will be studied using ASD patient-derived cortical organoids along with genome engineering, structural assays, and single-cell informatics to identify the cellular and molecular mediators of mTOR-related abnormal developmental phenotypes. These findings will yield insight into the mechanisms through which aberrant mTOR signaling can alter both adult behavior and early neurodevelopment. The proposal also aims to determine whether the two factors interact by examining patient- derived organoids exposed to media containing inflammatory mediators. This potential gene-environment interaction converging on mTOR signaling could reveal significant mechanistic overlap that may guide future studies seeking to understand human ASD biology in the contexts of environmental and genetic perturbations related to the mTOR pathway. These studies will take place at the University of California, Los Angeles. Relevant research centers include the Intellectual and Developmental Disabilities Research Center (IDDRC), the Jonsson Comprehensive Cancer Center (JCCC), and the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research (BSCRC). The applicant is enrolled in the UCLA Medical Scientist Training Program (MSTP) and will proceed to finish clinical training after defending his PhD thesis.

项目总结 自闭症谱系障碍(ASD)是一个巨大的个人、家庭和社会负担。他们的生活 患者及其家人也受到重大影响，因为生物、心理和社会影响通常会损害 在多个环境中运行。目前，治疗方法主要集中在行为疗法上。 由于致病机制的多样性和缺乏可靠性，生物治疗一直是具有挑战性的。 生物标志物。为了应对这一挑战，关键是要发现潜在的共同致病机制。 多个ASD风险因素，因为这样的了解最终可能有助于制定治疗策略 一群群病人。在ASD患者的一个子集中研究过的一个候选通路是PI3K-AKT- MTOR途径。有证据表明，这一途径可以通过对两种基因的反应而变得失调 以及环境影响，尽管与ASD的机制联系尚不清楚。这项建议旨在 检查一个环境(在子宫内暴露于母体炎症)和一个基因(杂合子 利用最新技术研究mTOR调节基因PTEN的突变和探测神经生物学现象 技巧。具体地说，暴露于成年小鼠的异常重复行为的持续性和可逆性 在Kornblum实验室开发的MIR小鼠模型中，将评估母体在子宫内的炎症， 使用单细胞信息学方法确定mTOR如何敏锐地调节神经元活动和 行为。此外，将使用ASD患者的皮质来研究与ASD可能的发育联系。 有机化合物以及基因组工程、结构分析和单细胞信息学来鉴定细胞 以及mTOR相关发育异常表型的分子介体。这些发现将产生 洞察异常mTOR信号可以改变成人行为和早期行为的机制 神经发育。该提案还旨在通过检查患者-确定这两个因素是否相互作用- 暴露在含有炎症介质的介质中的衍生有机化合物。这种潜在的基因环境 融合在mTOR信号上的相互作用可能揭示出重大的机制重叠，这可能会指导未来 在环境和遗传扰动的背景下寻求了解人类ASD生物学的研究 与mTOR途径相关。这些研究将在加州大学洛杉矶分校进行。 相关研究中心包括智力和发展障碍研究中心(IDDRC)， 琼森综合癌症中心(JCCC)和Eli&Edythe Bright再生中心 医学与干细胞研究(BSCRC)。申请者参加了加州大学洛杉矶分校的医学科学家培训 计划(MSTP)，并将继续完成临床培训后，他的博士论文。