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.

项目摘要 自闭症谱系障碍（ASD）是一个巨大的个人，家庭和社会负担。的生活 患者及其家属也受到严重影响，因为生物心理社会效应通常会损害 在多个环境中运作。目前，治疗方法主要集中在行为疗法，因为发展 由于致病机制的可变性和缺乏可靠的 生物标志物。为了应对这一挑战，至关重要的是要揭示共同的致病机制， 多个ASD风险因素，因为这样的理解最终可以帮助制定治疗策略， 患者群体。已经在ASD患者亚组中研究的一种候选途径是PI 3 K-AKT-1。 mTOR通路。有证据表明，这一途径可以成为失调，在响应两个遗传 和环境影响，尽管与ASD的机械联系尚不清楚。这项建议旨在 检查一个环境（在子宫内暴露于母体炎症）和一个遗传（杂合子 PTEN突变）调节mTOR和探针神经生物学现象 技术.具体来说，暴露于环境中的成年小鼠异常重复行为的持续性和可逆性 将在Kornblum实验室开发的MIR小鼠模型中评估母体子宫内炎症， 使用单细胞信息学方法来确定mTOR如何急性调节神经元活性， 行为此外，将使用ASD患者衍生的皮质类固醇研究ASD的可能发育联系。 类器官沿着基因组工程、结构分析和单细胞信息学来鉴定细胞 以及mTOR相关异常发育表型的分子介导物。这些发现将产生 深入了解异常mTOR信号传导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来确定这两个因素是否相互作用- 衍生的类器官暴露于含有炎症介质的介质。这种潜在的基因环境 mTOR信号传导的相互作用可以揭示可能指导未来的重要机制重叠， 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通路有关。这些研究将在洛杉矶的加州大学进行。 相关的研究中心包括智力和发育障碍研究中心（IDDRC）， Jonsson综合癌症中心（JCCC）和Eli & Edythe Broad再生中心 医学和干细胞研究（BSCRC）。申请人参加了加州大学洛杉矶分校医学科学家培训 程序（MSTP），并将继续完成临床培训后，捍卫他的博士论文。