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; 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）占了一个巨大的个人，家族和社会负担。生命 患者及其家人也受到显着影响，因为生物心理社会影响通常会损害 在多个设置中运行。当前，治疗方法以自行为治疗为重点 由于因果机制的可变性和缺乏可靠的可靠性，生物治疗一直在挑战 生物标志物。为了应对这一挑战，至关重要 多种ASD风险因素，因此这种理解最终可以帮助制定更大的治疗策略 一组患者。 PI3K-AKT-在一部分ASD患者中进行了研究的候选途径是 mtor途径。有证据表明，该途径可能会因两个遗传而失调 尽管与ASD的机理联系尚不清楚，但环境影响和环境影响。该提议试图 检查一种环境（子宫内母体炎症）和一个遗传（杂合子 使用最先进的MTOR和探针神经生物学现象调节的突变 技术。具体而言，成年小鼠暴露的异常重复行为的持久性和可逆性 子宫内的母体炎症将在Kornblum Lab中开发的miR小鼠模型中进行评估， 使用单细胞信息学方法来确定MTOR如何急性调节神经元活动和 行为。此外，将使用ASD患者衍生的皮质研究对ASD的可能发育链接进行研究 器官以及基因组工程，结构测定和单细胞信息学以识别细胞 和MTOR相关异常发育表型的分子介体。这些发现将产生 深入了解异常信号传导可以改变成人行为和早期的机制 神经发育。该提案还旨在确定这两个因素是否通过检查患者的相互作用 - 暴露于含有炎症介质的培养基的类器官。这种潜在的基因环境 MTOR信号转化的相互作用可能揭示出明显的机械重叠，这可能指导未来 试图在环境和遗传扰动的背景下了解人ASD生物学的研究 与MTOR通路有关。这些研究将在加利福尼亚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＆Edyth的再生中心 医学和干细胞研究（BSCRC）。申请人参加了UCLA医学科学家培训 计划（MSTP），并将在捍卫其博士学位论文后继续完成临床培训。