Epidemiologic identification and mechanistic investigation of early life environmental risk factors for eosinophilic esophagitis

嗜酸性粒细胞性食管炎早期环境危险因素的流行病学识别及机制研究

• 批准号: 10373071
• 负责人: Evan Samuel Dellon
• 金额: $ 63.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373071
• 关键词: 3-Dimensional; Abdominal Pain; Address; Adolescent; Adult; Allergens; Amoxicillin; Antibiotics; Architecture; Azithromycin; Barium; Biological Assay; Biological Markers; Biology; Breast Feeding; Calpain; Caring; Case-Control Studies; Cephalexin; Child; Childhood; Clinical; Data; Deposition; Development; Diagnosis; Disease; Environmental Exposure; Environmental Risk Factor; Eosinophilic Esophagitis; Epidemiology; Epithelial; Esophageal Dysphagia; Esophageal Stenosis; Esophageal mucous membrane; Esophagus; Etiology; Exogenous Factors; Exposure to; Failure to Thrive; Food; Future; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Healthcare; Heartburn; Human; Human Milk; Immune; Impairment; Incidence; Individual; Infiltration; Investigation; Knowledge; Laboratories; Lead; Life; Link; Measurement; Measures; Mediating; Methodology; Methods; Modeling; Molecular; Morbidity - disease rate; Pathogenesis; Patients; Peptide Hydrolases; Predisposition; Prevalence; Research; Research Design; Risk; Risk Factors; Science; Susceptibility Gene; TLR2 gene; Techniques; Toll-like receptors; Tooth structure; United States; Vomiting; archive data; archived data; care burden; design; disorder prevention; early life exposure; eosinophil; epidemiology study; fetal; gastrointestinal; gene environment interaction; individual patient; innovation; interest; microbial; microbiome; multidisciplinary; new therapeutic target; novel; risk variant; sample archive; toxicant

Epidemiologic identification and mechanistic investigation of early life environmental risk factors for eosinophilic esophagitis ABSTRACT Eosinophilic esophagitis (EoE) is a recently recognized immune-mediated disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to failure to thrive, abdominal pain, vomiting, and heartburn in children, and progressing to esophageal stenosis and food impaction in adults. Though initially thought to be rare, the incidence and prevalence are rising dramatically, and over the past decade EoE has rapidly become a major cause of upper gastrointestinal morbidity. Despite increases in the understanding of the condition, it is currently not possible to determine why individual patients develop EoE. This is frustrating for patients and practitioners alike. EoE is considered to be an immune/allergen-mediated disease, and epidemiologic studies support a primarily environmental etiology. However, environmental risk factors have not been extensively studied in EoE, and prior studies, including by our own group, are limited by a crude assessment of exposures, recall bias, inability to assess fetal biomarkers, and lack of mechanistic understanding. Our goal is to address this knowledge gap by using an innovative method to precisely measure early life exposures in deciduous (primary, or “baby”) teeth that may be implicated in EoE development. Of particular interest are early life antibiotic exposure and duration and intensity of breastfeeding (which can be derived from barium levels in teeth). Increased antibiotic exposure and decreased breastfeeding have been linked to risk of atopic diseases. Measuring selected environmental exposures in teeth has never been applied to EoE, but we have documented the feasibility of this approach. This assessment, together with the use of novel cellular and molecular techniques for elucidating the mechanisms underlying the effects of these early life exposures, has the potential to greatly enhance our understanding of the pathogenesis of EoE. Our hypothesis is that the risk of EoE related to early life exposures is primarily due to an impaired esophageal epithelial barrier, and that genetic susceptibility will interact with the exposures to modify risk. The specific aims are to 1) determine the association between early life antibiotic exposure and EoE; 2) determine whether breastfeeding is associated with EoE, and evaluate whether the susceptibility genotype for CAPN14 modifies the association between breastfeeding and EoE; and 3) determine the functional significance and mechanisms of early life exposures on esophageal epithelial architecture and barrier function. To achieve these aims, we will conduct a case-control study to characterize temporal exposures, and in parallel will perform mechanistic analyses. This innovative, hypothesis-driven, and rigorously designed study will lead to robust and unbiased results. It will be conducted by a multidisciplinary team with recognized expertise in EoE, epidemiology, clinical/translational/lab research, and exposure science. The results will have a major impact on the understanding of EoE etiology and by potentially identifying opportunities for disease prevention which could lead to the development of new treatment options.

早期生活的流行病学识别和机械投资的早期环境风险因素 嗜酸性静脉炎 抽象的 嗜酸性食管炎（EOE）是最近公认的免疫介导的疾病，由异常定义 将嗜酸性粒细胞浸润到食管粘膜中，导致腹部疼痛，呕吐和 儿童的胃灼热，并发展为成年人的食管狭窄和食物的影响。虽然最初 人们认为这是罕见的，事件和流行率急剧上升，在过去的十年中 迅速成为上胃肠道发病率的主要原因。尽管有所了解 这种情况，目前无法确定个别患者为什么发展EOE。这很令人沮丧 适用于患者和从业者。 EOE被认为是一种免疫/过敏原介导的疾病， 流行病学研究支持主要的环境病因。但是，环境风险因素具有 没有在EOE中进行广泛研究，包括我们自己的小组在内的先前研究受到原油的限制 评估暴露，召回偏见，无法评估胎儿生物标志物以及缺乏机理 理解。我们的目标是通过使用创新方法来精确衡量这一知识差距 EOE发育中可能暗示的决定性（主要或“婴儿”）牙齿的早期生活暴露。的 特别感兴趣的是早期寿命抗生素暴露，母乳喂养的持续时间和强度（这可以是 源自牙齿中的钡水平）。抗生素暴露和改善的母乳喂养已经增加了 与特应性疾病的风险有关。从未应用牙齿中选定的环境暴露 对EOE，但我们已经记录了这种方法的可行性。该评估以及使用 新型的细胞和分子技术，以阐明这些早期作用的基础机制 生命暴露，有可能大大增强我们对EOE发病机理的理解。我们的 假设是，EOE与早期生活暴露有关的风险主要是由于食管的受损 上皮障碍和遗传敏感性将与改变风险的暴露相互作用。具体 目的是1）确定早期抗生素暴露与EOE之间的关联； 2）确定是否 母乳喂养与EOE相关，并评估CAPN14修饰符的易感性基因型是否 母乳喂养与EOE之间的关联； 3）确定功能意义和机制 关于食管上皮结构和障碍功能的早期生活暴露。为了实现这些目标，我们 将进行一项病例对照研究以表征临时暴露，并同时执行机械 分析。这项创新，假设驱动且设计严格设计的研究将导致坚固而公正 结果。它将由一个多学科团队进行，在EOE，流行病学， 临床/转化/实验室研究和暴露科学。结果将对 对EOE病因的理解以及潜在地识别预防疾病的机会 导致开发新的治疗选择。