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: 10806422
• 负责人: Jennifer Lisa Ames
• 金额: $ 24.9万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10806422
• 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 Variation; Genomics; Genotype; Goals; Heterogeneity; Immune; Immune Targeting; Immune system; Immunologic Markers; Immunologics; Immunology; Individual; Infant; Inflammation; Intervention; Investigation; Joints; Knowledge; Life; Link; Mediating; Mediation; Medical; Mentors; Mentorship; Metabolic; Methodology; Methods; Modeling; Mothers; Neonatal; Pathway interactions; Perinatal; Phase; Phenotype; Physiological; Physiology; Placenta; 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 association; cohort; developmental disease; environmental chemical; epidemiology study; fetal; gene environment interaction; genetic risk factor; 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; pharmacologic; placental transfer; pollutant; polygenic risk score; population based; 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.

抽象的 儿童自闭症谱系障碍（ASD）的患病率上升是一个公共卫生问题。一个 在ASD的发展中已经实施了扩大遗传和环境风险因素的景观， 表明早期的复杂，多因素的起源。许多内分泌干扰化学物质（EDC）具有 神经毒性潜力，但它们在ASD发展中的作用需要澄清。 EDC与母亲有关 免疫失调和炎症，这是ASD发育起源的主要研究假设。基因- EDC的环境调查，重点是合理的生物学机制，可以提供关键 深入了解个体的遗传亚组是否可能对环境化学物质更敏感 对ASD和EDC之间的这一不一致的证据提出清晰度。拟议的研究试图结合 多基因且复杂的环境混合物的方法来解决对ASD的理解差距 病因。在此奖项的K99阶段，我将进行自闭症的教学和修改培训 分析的复杂环境混合物，全基因组的流行病学，免疫学和方法 数据和基因环境相互作用。在一个有历史的强大多学科团队的精神状态下 协作，我将将这种培训应用于环境，免疫学和 自闭症研究早期标记的遗传数据（EMA； R01ES016669，PI：CROEN），一种基于人群的 病例对照研究（n = 1005）。在AIM 1中，我将在复杂混合方法中应用培训来检查 在妊娠期间关节暴露于多个EDC的途径，母体和新生儿的生物标志物 免疫功能和儿童ASD。在AIM 2中，我将在全基因组分析中应用培训，以识别母亲和 胎儿遗传变异与EDC的混合物相关的孕妇循环中的混合物。在K00阶段（AIM 3）， 我将利用这些新的分析技能来对EDC和多基因的关联进行GXE分析 风险早期生命免疫释放功能和ASD发展。我将在EMA中执行AIM 3，并重复两次 较大的母子队列研究。这项研究的长期目标是确定可修改的风险因素和 ASD中的关键生物学途径不仅可以告知干预措施以降低神经毒性暴露 怀孕的母亲和婴儿，以及针对免疫和其他生理学的药物干预措施 中间人。这些培训和研究活动将成为发展竞争性的跳板 R01应用程序并启动了我自闭症流行病学独立职业。