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Natural History of Viral Induced Airway Dysfunction and Asthma in Minority Children

少数民族儿童病毒引起的气道功能障碍和哮喘的自然史

基本信息

批准号：
10021680
负责人：
Esteban Gonzalez Burchard
金额：
$ 207.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021680
关键词：
3 year old Address Affect African American Age Asthma Birth Bronchiolitis Child Childhood Childhood Asthma Clinical Data Collaborations Data Development Diagnosis Disease Environment Ethnic Origin Ethnic group Etiology Exhibits Expression Profiling Functional disorder Gene Expression Gene Expression Profile Genes Genetic Genetic Determinism Genetic Predisposition to Disease Health Policy Human Incidence Infant Infection Infrastructure Life Longitudinal Studies Metagenomics Mexican Americans Minority Molecular Monitor Morbidity - disease rate Natural History Newborn Infant Nose Participant Plant Roots Population Prevalence Prospective Studies Public Health Publications Puerto Rican Puerto Rico Race Recurrence Reporting Research Respiratory Signs and Symptoms Respiratory Syncytial Virus Infections Respiratory syncytial virus Rhinovirus Risk Risk Factors Seasons Seminal Severities Standardization Swab Testing Variant Viral Viral Respiratory Tract Infection Virus Virus Diseases Wheezing Work airway epithelium base case control clinical practice cohort design early childhood epidemiology study gene environment interaction genome-wide health care service utilization high risk population injured longitudinal analysis minority children minority subjects mortality novel racial and ethnic recruit respiratory respiratory infection virus response risk variant social transcriptome transcriptomics virus genetics

项目摘要

PROJECT SUMMARY/ABSTRACT Asthma prevalence in Puerto Ricans is 37% versus 12% for whites yet most studies have been conducted among the latter. This asthma burden extends to asthma morbidity and mortality, which are 2.4- and 4-fold higher among Puerto Ricans compared to whites, respectively. There is a strong association between severe, early-life viral respiratory illnesses and development of childhood recurrent wheeze and asthma. However, little is known about the mechanisms underlying these associations. Does airway dysfunction exist at birth and first manifest in early life as a severe illness in response to viral respiratory infections, and later as childhood asthma? Or does a severe, early-life respiratory illness injure a normal airway and precipitate asthma later in childhood? We will study Puerto Rican children to address these questions via three Specific Aims. Aim 1: Recruit a cohort of 3,000 newborns to longitudinally study the effects of early-life viral respiratory illnesses on nasal airway molecular endotype and risk for recurrent wheeze. We will collect yearly environmental, social, and clinical data on each participant and track all respiratory illnesses from birth to age 3. We will record severity and presence of wheezing in each child's illnesses and collect nasal swabs to determine the presence/type of virus associated with these illnesses. Aim 2: Identify viral and genetic determinants of severe early-life respiratory illnesses and whether the molecular state of the nasal airway epithelium at birth is predictive of these severe illnesses. We will perform transcriptomic and viral analyses on nasal airway swabs from subjects at birth and during respiratory illness. We will test if severe respiratory illnesses are associated with viral infection in general and/or infection with a specific viral species. We will use genome-wide genetic data to identify risk variants for severe early-life respiratory illnesses and variants influencing airway gene expression at birth and during illness (eQTLs). We will test for GxE interactions between top risk variants/eQTLs and infection with different viral species. We will also identify gene expression response to mild vs. severe early-life respiratory illnesses and determine if airway gene expression at birth is predictive of severe respiratory illness in early childhood. Aim 3: Determine the relationship between severity of early-life respiratory illness and post-illness but pre-asthma nasal airway gene expression profiles. We will perform transcriptomic and viral metagenomic analysis of nasal swabs collected from subjects at age 3. We will determine how severe respiratory illnesses affect the trajectory of airway gene expression profiles from birth to early childhood. Finally, we will determine if mild or severe respiratory illness in early life is predictive of recurrent wheeze at age 3. Our longitudinal birth cohort will [1] be the largest prospective study of minority infants, [2] provide novel and seminal information on genetic/viral risk factors for severe respiratory illnesses, and [3] identify airway endotypes that high-risk groups exhibit at birth and after respiratory illness, but prior to asthma onset. Our study will help to elucidate the relationship between early-life respiratory illness and asthma.

项目概要/摘要波多黎各人的哮喘患病率为 37%，而白人的哮喘患病率为 12%，但大多数研究均已进行其中。这种哮喘负担导致哮喘发病率和死亡率分别是原来的 2.4 倍和 4 倍与白人相比，波多黎各人的比例分别更高。严重程度之间有很强的关联性，生命早期的病毒性呼吸道疾病以及儿童反复喘息和哮喘的发展。然而，很少了解这些关联背后的机制。出生时和刚出生时是否存在气道功能障碍在生命早期表现为对病毒性呼吸道感染的严重疾病，随后在儿童时期表现为哮喘？或者，生命早期严重的呼吸系统疾病会损害正常气道并在以后引发哮喘吗？童年？我们将研究波多黎各儿童，通过三个具体目标来解决这些问题。目标 1：招募 3,000 名新生儿组成的队列，纵向研究生命早期病毒性呼吸道疾病对新生儿的影响鼻气道分子内型和反复喘息的风险。我们将收集年度环境、社会、以及每个参与者的临床数据，并跟踪从出生到 3 岁的所有呼吸道疾病。我们将记录每个孩子疾病的严重程度和喘息的存在，并收集鼻拭子以确定与这些疾病相关的病毒的存在/类型。目标 2：确定重症的病毒和遗传决定因素生命早期呼吸系统疾病以及出生时鼻气道上皮的分子状态是否可以预测这些严重的疾病。我们将对鼻气道拭子进行转录组和病毒分析来自出生时和呼吸道疾病期间的受试者。我们将测试是否与严重呼吸道疾病有关一般病毒感染和/或特定病毒种类感染。我们将使用全基因组遗传用于识别严重生命早期呼吸系统疾病的风险变异和影响气道基因的变异的数据出生时和患病期间的表达（eQTL）。我们将测试最高风险之间的 GxE 交互变异/eQTL 和不同病毒种类的感染。我们还将确定对轻度的基因表达反应与严重的早期呼吸系统疾病相比，并确定出生时的气道基因表达是否可以预测儿童早期患有严重的呼吸道疾病。目标 3：确定早年严重程度之间的关系呼吸系统疾病和病后但哮喘前的鼻气道基因表达谱。我们将表演对 3 岁时收集的受试者鼻拭子进行转录组和病毒宏基因组分析。我们将确定严重的呼吸道疾病如何影响从出生到气道基因表达谱的轨迹幼儿期。最后，我们将确定生命早期的轻微或严重呼吸道疾病是否预示着 3 岁时反复喘息。我们的纵向出生队列将 [1] 成为针对少数族裔的最大的前瞻性研究婴儿，[2]提供有关严重呼吸道疾病的遗传/病毒危险因素的新颖和开创性的信息， [3] 识别高危人群在出生时和呼吸系统疾病之后、但在患病之前表现出的气道内型哮喘发作。我们的研究将有助于阐明早期呼吸系统疾病与哮喘之间的关系。