Interactions between Environmental Microbiome, Maternal Immunity, Neonatal Epigenome and Respiratory Microbiome Development as Determinants of Asthma In Childhood

环境微生物组、母体免疫力、新生儿表观基因组和呼吸道微生物组发育之间的相互作用是儿童哮喘的决定因素

• 批准号: 9395215
• 负责人: Susan Veronica Lynch
• 金额: $ 24.37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395215
• 关键词: 1 year old; AIDS/HIV problem; Address; Age; Allergic; Allergic Disease; Antibiotics; Asthma; Biological Assay; Birth; Cells; Characteristics; Child; Childhood; Childhood Asthma; Chronic Disease; Chronology; Communities; Consumption; Cues; DNA Methylation; Data; Development; Disease; Disease Outcome; Economic Burden; Environmental Exposure; Environmental Tobacco Smoke; Epidemiology; Event; Exhibits; Exposure to; FOXP3 gene; Farming environment; Fever; Genetic; House Dust; Hypermethylation; Hypersensitivity; IL2RA gene; IL4 gene; IgE; Immune; Immunity; Infant; Infection; Interferons; Interleukin-13; Knowledge; Lead; Life; Lipids; MADH3 gene; Maternal Exposure; Mediterranean Diet; Meta-Analysis; Metabolism; Microbe; Mitogens; Mothers; Nature; Neonatal; Nursery Schools; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Plant Roots; Play; Predisposition; Pregnancy; Recording of previous events; Relative Risks; Risk; Risk Factors; Role; Sampling; Smoking; Stress; Structure; Taxonomy; Testing; Third Pregnancy Trimester; Time; Tuberculosis; Umbilical Cord Blood; Water; Weight; Wheezing; asthmatic; base; cohort; disorder risk; emerging adult; epigenome; flu; gut microbiota; in utero; inner city; methylome; microbial; microbial community; microbiome; microbiota; neonate; novel; offspring; persistent symptom; postnatal; pregnant; prenatal; prenatal exposure; promoter; respiratory; response; study population

Asthma is the most common chronic disease of childhood, with an economic burden that exceeds that of tuberculosis and HIV/AIDS combined. Epidemiologic evidence suggests that the origins of disease occur during pre-school years even when chronic symptoms appear in early adulthood. Moreover, several risk factors for childhood asthma suggest that the disease may have its beginnings already in utero, and the maternal milieu during pregnancy may contribute to disease risk. These data suggest that the trajectory to childhood asthma and related outcomes (e.g., allergic sensitization, wheeze) may begin prenatally, when maternal environmental exposures calibrate set points for responses to post-natal environmental cues. Our preliminary data (mostly collected in our birth cohort, the Infant Immune Study: IIS) suggest that mechanisms rooted in the environmental microbiome, the maternal immune milieu, the child's immune epigenome at birth and early-life microbiota play a prominent role in this trajectory: a) microbial community structure in house dust is associated with asthma-related outcomes; b) the maternal prenatal immune milieu (expressed as the ratio between the amounts of IFN and IL13 produced by mitogen-stimulated maternal PBMC isolated during the third trimester of pregnancy) influences asthma risk in the child; c) DNA methylation in cord blood immune cells from IIS neonates is associated with the maternal prenatal immune milieu (IFN:IL13 ratio) to which the child was exposed in utero; d) the neonatal methylome differs in children who do and do not become asthmatic by age 9, and SMAD3 hypermethylation predicts asthma selectively in children born to asthmatic mothers; e) neonatal microbiome perturbation is associated with significantly different relative risk of allergy at age 2 and asthma at age 4. The nature and chronology of these events lead us to hypothesize that the pregnant mother's immune profile, influenced by environmental exposures, modifies the child's epigenome in utero, postnatal airway microbiome development, and the trajectory to allergy and asthma during childhood. To test this hypothesis, we will leverage abundant existing information and well-characterized, banked samples from the IIS population. We propose to characterize the child's immune methylome at birth and its relationships with the prenatal maternal immune milieu (IFN:IL13 ratio), respiratory microbiota development, and asthma and allergic disease outcomes from birth to age 9 yrs (Specific Aim 1); and to characterize environmental (house dust) microbial exposures and post-natal (<1 year old) respiratory microbiota and to assess their relationship with maternal prenatal immune profile, neonatal epigenome, and child's risk for asthma, allergy and related outcomes from birth to age 9 yrs (Specific Aim 2). To our knowledge, this is the first time that a single study examines all of these characteristics and their mutual relations in the context of childhood asthma and allergy. This proposal aims to fill this gap in knowledge to address the role of the hypothesized causal pathway in the development of childhood disease.

哮喘是儿童最常见的慢性疾病，其经济负担超过 结核病和艾滋病毒/艾滋病加在一起。流行病学证据表明，疾病的起源发生在 即使在成年初期出现慢性症状的学龄前儿童也是如此。此外，几个风险因素 儿童哮喘表明，这种疾病可能在子宫中就已经开始了，母体环境也是如此 怀孕期间可能会增加疾病风险。这些数据表明，儿童哮喘的发展轨迹 和相关的结果(如过敏、喘息)可能在产前就开始了，当母亲 环境暴露校准了对出生后环境提示做出反应的设定点。 我们的初步数据(主要收集在我们的出生队列中，婴儿免疫研究：IIS)表明 根植于环境微生物群、母体免疫环境、儿童免疫的机制 出生时的表观基因组和早期的微生物群在这一轨迹中起着突出的作用：a)微生物群落 房屋灰尘中的结构与哮喘相关的结局有关；b)母体产前免疫环境 (表示为有丝分裂原刺激的母亲外周血单核细胞产生干扰素和白介素13之间的比率 (C)脐带DNA甲基化 新生儿血免疫细胞与母体产前免疫环境(干扰素/白介素13比率)相关 孩子在子宫中接触到的；d)新生儿的甲基组在有和没有成为的儿童中不同 9岁时哮喘，Smad3高甲基化可选择性地预测哮喘儿童的哮喘 母亲；e)新生儿微生物群紊乱与以下年龄段过敏的相对风险显著不同有关 2岁和4岁时患哮喘。 这些事件的性质和时间顺序让我们假设怀孕的母亲对 受环境暴露影响的特征，在子宫内、出生后修改儿童的表观基因组 呼吸道微生物群的发育，以及儿童时期过敏和哮喘的轨迹。为了测试这一点 假设，我们将利用来自IIS的丰富的现有信息和特征良好的银行样本 人口。我们建议描述儿童出生时的免疫甲基组及其与 产前母体免疫环境(干扰素/白介素13比率)、呼吸道微生物区系发育、哮喘和变态反应 从出生到9岁的疾病结局(具体目标1)；以及环境特征(房屋粉尘) 微生物暴露和出生后(1岁)呼吸道微生物区系，并评估它们与 母体产前免疫状况、新生儿表观基因组与儿童哮喘、过敏及相关结局的风险 从出生到9岁(具体目标2)。据我们所知，这是第一次一项研究检查所有 在儿童哮喘和过敏的背景下，研究这些特征及其相互关系。这项建议 旨在填补这一知识空白，以解决假设的因果路径在儿童精神疾病发展中的作用 儿童疾病。