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 儿童中自闭症谱系障碍 (ASD) 患病率的上升是一个公共健康问题。一个 遗传和环境风险因素的不断扩大与自闭症谱系障碍的发展有关， 表明早期生命的复杂、多因素起源。许多内分泌干扰化学物质 (EDC) 潜在的神经毒性，但它们在 ASD 发展中的作用需要澄清。 EDCs 与母体有关 免疫失调和炎症，这是自闭症谱系障碍发育起源的一个主要研究假设。基因- 对 EDC 进行环境调查，重点关注合理的生物机制，可以提供关键的信息 深入了解个体的遗传亚群是否可能对环境化学物质更敏感，以及 澄清 ASD 和 EDC 之间不一致的证据。拟议的研究旨在结合 多基因和复杂的环境混合物方法来解决对自闭症谱系障碍的理解差距 病因学。在该奖项的 K99 阶段，我将进行自闭症方面的教学和指导培训 流行病学、免疫学以及分析复杂环境混合物、全基因组的方法 数据以及基因与环境的相互作用。在强大的多学科团队的指导下 合作，我将把这次培训应用于环境、免疫学和 来自自闭症早期标记研究（EMA；R01ES016669，PI：Croen）的遗传数据，这是一项基于人群的研究 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培训来检查 妊娠期间联合暴露于多种 EDC、孕产妇和新生儿生物标志物之间的途径 免疫功能和儿童自闭症谱系障碍。在目标 2 中，我将应用全基因组分析培训来识别母亲和 与妊娠中期循环中 EDC 混合物相关的胎儿遗传变异。在 K00 阶段（目标 3）， 我将利用这些新的分析技能对 EDC 和多基因的关联进行 GxE 分析 生命早期免疫功能和 ASD 发展的风险。我将在 EMA 中进行目标 3，并进行两次复制 更大规模的母子队列研究。这项研究的长期目标是确定可改变的风险因素和 ASD 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 怀孕的母亲和婴儿，以及针对免疫和其他生理功能的药物干预 中间体。这些培训和研究活动将作为发展具有竞争力的跳板 R01 申请并开始我在自闭症流行病学方面的独立职业生涯。