Microbiome Influences on Asthma-Related Outcomes in Early Life

微生物组对生命早期哮喘相关结果的影响

• 批准号: 10214523
• 负责人: Fernando D Martinez
• 金额: $ 48.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214523
• 关键词: 17q; Admixture; Affect; Age; Age-Months; Arizona; Asthma; Birth; Cells; Characteristics; Child; Child Development; Childhood; Childhood Asthma; Chromosomes; Chronic Disease; DNA Methylation; Data; Development; Dust; Environment; Environmental Exposure; Epigenetic Process; Exposure to; Farming environment; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Home environment; House Dust; Immune; Immune response; Immune system; Immunologics; Infant; Infant Development; Inflammation; Life; Link; Livestock; Locales; Location; Measures; Mediating; Mexican; Mexican Americans; Mexico; Microbe; Microbiology; Modality; Mothers; Neonatal; Outcome; Participant; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Population; Preventive; Respiratory Tract Infections; Rhinovirus; Ribosomal RNA; Risk; Source; Systems Development; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; Urban Population; Vagina; Variant; Water; Wheezing; cohort; cytokine; disorder risk; drinking water; early childhood; early life exposure; epigenome; genomic locus; gut colonization; gut microbiome; gut microbiota; innovation; maternal microbiota; methylation pattern; microbial; microbial colonization; microbiome; microbiome research; microbiota; multiple omics; neonate; pet animal; prenatal; prospective; recruit; respiratory; response; risk variant; single cell analysis; transcriptome; urban setting; vaginal microbiota

BEAMS ABSTRACT: Project 1 Observations by our group and others indicate that risk for asthma originates very early in life. Some of the implicated early childhood environmental exposures, such as to farms and pets, can inform establishment and development of the gut microbiome in the neonate. This in turn may affect asthma risk through influencing both the child’s immune development and response to respiratory infections such as those due to rhinovirus. Maternal prenatal factors, including immunological phenotype and microbiota, similarly may influence development of the child’s microbiota and asthma risk. We recently showed that Mexican-American schoolchildren living in Tucson, AZ, have a fourfold higher rate of asthma than those living in nearby Nogales, Mexico (MX). We also showed that infants born in Tucson and Nogales, MX, who are ancestrally related, are exposed to dramatically different home environments and have differential gut microbiota characteristics at 1 month of age. We postulate that exposure to specific microbial taxa in Nogales, MX may account for the relative protection against asthma as compared to Tucson, and that this protection is mediated by differential seeding of the infant’s gut microbiota in Tucson as compared to Nogales, MX. Project 1 of BEAMS will identify divergent early-life microbial and immune developmental trajectories associated with asthma protection in Nogales, MX compared with Tucson, AZ, and the microbiota exposures that promote them. Aim 1 will identify maternal factors related to asthma protection, including characteristics of maternal (gut, vagina) and environmental (dust, water) sources of differentially present microbiota, as well as immunologic characteristics which may relate to these exposures. We will extensively phenotype these PBMCs using multiplexed cytokine panels and CyTOF, to identify cellular phenotypes and characteristics that relate to exposures, location, and asthma outcomes in the child. Finally, we will identify differential DNA methylation patterns from cord blood collected during delivery that relate to the transborder differential microbiota and immune outcomes. Aim 2 will identify infant gut microbiota, environmental and maternal factors, and infant immune cellular characteristics and phenotypes related to asthma protection, in early life and longitudinally, using as an early asthma-related outcome the presence of wheezing with type 2 inflammation (T2 Wheezing, T2W) at age 2. Further, we will use single-cell analyses to identify differential cellular transcription and development related to location and in response to ex-vivo stimulation with rhinovirus. Aim 3 will identify the specific microbial exposures that may modulate the association between polymorphisms in the asthma risk locus at chromosome 17q and wheezing lower respiratory illnesses at each location. This innovative project utilizes a longitudinal, multiple-omics approach to identify potential microbiological and immunological pathways by which exposure to dramatically different urban environments, prenatally through early-life, may be associated with asthma protection or risk.

梁摘要：项目1 我们小组和其他人的观察表明，哮喘的风险在生命的早期就起源于。 涉及幼儿环境暴露，例如农场和宠物，可以告知机构和 新生儿中的肠道微生物组的发展可能会影响两者 儿童的免疫发育和对呼吸道不症的反应，例如由于鼻病毒。 产前因素，包括免疫学免疫学表型和微生物群，可能会影响您的发展 儿童的微生物群和哮喘风险。 AZ比墨西哥附近的Nogales（MX）的哮喘率高四倍 与祖先相关的MX的图森和诺加莱斯出生的婴儿与急剧不同 家居环境，在1个月大时具有不同的肠道微生物群 暴露于Nogales的特定微生物类群 与图森（Tucson）相比，保护是由婴儿在 与Nogales相比 与Nogales，MX相比，与哮喘保护相关的免疫发育轨迹与。 图森，亚利桑那州和微生物群促进它们。 哮喘保护，母体（肠道，阴道）的包含特征和环境（灰尘，水）的来源 可能与这些暴露有关的差异性微生物群以及不动特性。 我们将使用多重细胞因子面板和细胞来广泛表型，以鉴定细胞 与儿童暴露，位置和哮喘结局有关的表型和特征。 将确定从分娩过程中收集的脐带血的差异DNA甲基化模式 跨晶菌群和免疫结果。 以及与哮喘保护相关的婴儿免疫特征和表型 早期生活和纵向，用作早期哮喘相关的结果，与2型喘息的存在 2岁时发炎（T2 Wheeezing，T2W）。此外，我们将使用细胞分析来识别差异 与位置有关的细胞转录和发育以及鼻病毒刺激的响应。 AIM 3将确定调节多态性之间关联的特定微生物暴露 在哮喘病中，染色体17q的基因座，并在每个位置喘息下呼吸道疾病 创新的项目利用纵向多词的方法来识别潜在的微生物学和 免疫学途径，通过产前暴露于急剧不同的城市环境中 早期生命可能与哮喘保护或风险有关。