Interactions of Environmental Chemical Mixtures, Genetics, and Immune Pathways in Autism Spectrum Disorder

自闭症谱系障碍中环境化学混合物、遗传学和免疫途径的相互作用

• 批准号: 10366050
• 负责人: Jennifer Lisa Ames
• 金额: $ 12.28万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366050
• 关键词: Address; Affect; American; Award; Behavioral; Biological; Biological Markers; Candidate Disease Gene; Case-Control Studies; Child; Chronic; Cohort Studies; Collaborations; Complex; Complex Mixtures; Data; Development; Dioxins; Endocrine; Endocrine Disruptors; Environment; Environmental Risk Factor; Epidemiology; Etiology; Exposure to; Financial cost; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Heterogeneity; Immune; Immune Targeting; Immune system; Immunologic Markers; Immunologics; Immunology; Individual; Infant; Inflammation; Intervention; Investigation; Joints; Knowledge; Lead; Life; Link; Mediating; Mediation; Medical; Mentors; Mentorship; Metabolic; Methodology; Methods; Modeling; Mothers; Neonatal; Pathway interactions; Perinatal; Pharmacology; Phase; Phenotype; Physiological; Physiology; Placenta; Plant Roots; Population Study; Positioning Attribute; Pregnancy; Pregnant Women; Prevalence; Public Health; Recording of previous events; Research; Research Activity; Risk; Risk Factors; Role; Sensory; Subgroup; Testing; Training; Training Activity; United States National Institutes of Health; Variant; Work; Xenobiotic Metabolism; autism spectrum disorder; autistic children; career; chemical genetics; cohort; developmental disease; disorder risk; environmental chemical; epidemiology study; fetal; gene environment interaction; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk; immune function; improved; inflammatory marker; insight; modifiable risk; multidisciplinary; neurotoxic; neurotoxicity; novel; pollutant; polygenic risk score; pregnancy circulation; prenatal; prenatal exposure; programs; public health relevance; screening; skills; social; targeted treatment; therapeutic target; tool

ABSTRACT The rising prevalence of Autism Spectrum Disorder (ASD) among children is a public health concern. An expanding landscape of genetic and environmental risk factors has been implicated in ASD’s development, indicating complex, multifactorial origins in early life. Many endocrine-disrupting chemicals (EDCs) have neurotoxic potential, but their role in ASD development needs clarification. EDCs are implicated in maternal immune dysregulation and inflammation, a leading research hypothesis of ASD’s developmental origins. Gene- environment investigations of EDCs, with focus on plausible biological mechanisms, could provide critical insight into whether genetic subgroups of individuals may be more sensitive to environmental chemicals and bring clarity to this inconsistent evidence between ASD and EDCs. The proposed research seeks to combine polygenic and complex environmental mixtures approaches to address gaps in understanding of ASD’s etiology. During the K99 phase of this award, I will pursue didactic and mentored training in autism epidemiology, immunology, and methodologies of analyzing complex environmental mixtures, genome-wide data, and gene-environment interplay. Under the mentorship of a strong multidisciplinary team with a history of collaboration, I will apply this training to studies of the relationships between environmental, immunologic, and genetic data from the Early Markers for Autism study (EMA; R01ES016669, PI: Croen), a population-based case-control study (n=1005). In Aim 1, I will apply training in complex mixtures methods to examine the pathway between joint exposure to multiple EDCs during gestation, biomarkers of maternal and neonatal immune function, and child ASD. In Aim 2, I will apply training in genome-wide analysis to identify maternal and fetal genetic variants associated with mixtures of EDCs in mid-pregnancy circulation. In the K00 phase (Aim 3), I will harness these new analytical skills to conduct a GxE analysis of the association of EDCs and polygenic risk on early life immune function and ASD development. I will conduct Aim 3 in EMA with replication in two larger mother-child cohort studies. The long-term goal of this research is to identify modifiable risk factors and key biological pathways in ASD which can inform not only interventions to lower neurotoxic exposures in pregnant mothers and infants but also pharmacologic interventions targeting the immune and other physiologic intermediates. These training and research activities will serve as the springboard for developing a competitive R01 application and launching my independent career in autism epidemiology.

摘要 自闭症谱系障碍（ASD）在儿童中的发病率不断上升，是一个公共卫生问题。一个 遗传和环境风险因素的扩展与ASD的发展有关， 表明早期生命的起源是复杂的多因素的许多内分泌干扰物（EDCs） 神经毒性潜力，但其在ASD发展中的作用需要澄清。内分泌干扰物与母体 免疫失调和炎症是ASD发育起源的主要研究假设。吉恩 环境调查的内分泌干扰物，重点是合理的生物机制，可以提供关键的 深入了解个体的遗传亚群是否对环境化学品更敏感， 澄清ASD和EDC之间的不一致证据。拟议的研究旨在将联合收割机 多基因和复杂的环境混合物的方法，以解决在理解ASD的差距 病因学在这个奖项的K99阶段，我将追求自闭症的教学和指导培训 流行病学，免疫学，分析复杂环境混合物的方法，全基因组 数据和基因环境相互作用。在一个强大的多学科团队的指导下， 合作，我将把这种训练应用到环境，免疫学和 来自自闭症早期标记研究（EMA; R 01 ES 016669，PI：Croen）的遗传数据，一项基于人群的 病例对照研究（n=1005）。在目标1中，我将应用复杂混合物方法的训练来检查 妊娠期联合暴露于多种内分泌干扰物之间的途径，母体和新生儿的生物标志物 免疫功能和儿童自闭症在目标2中，我将应用全基因组分析的培训，以确定孕产妇和 与妊娠中期循环中内分泌干扰物混合物相关的胎儿遗传变异。在K 00阶段（目标3）， 我将利用这些新的分析技能，对内分泌干扰物和多基因相关性进行GxE分析。 早期免疫功能和ASD发展的风险。我将在EMA进行目标3，并在两个 更大规模的母婴队列研究。这项研究的长期目标是确定可改变的风险因素， ASD中的关键生物学途径，不仅可以为降低神经毒性暴露的干预措施提供信息， 孕妇和婴儿，以及针对免疫和其他生理的药物干预， 中间体的这些培训和研究活动将成为发展具有竞争力的 R 01应用程序和启动我在自闭症流行病学的独立职业生涯。