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.

新生儿早期环境危险因素的流行病学鉴定和机制研究 嗜酸性食管炎 摘要 嗜酸性粒细胞性食管炎（EoE）是近年来发现的一种免疫介导的疾病， 嗜酸性粒细胞浸润到食管粘膜中，导致无法生长、腹痛、呕吐，以及 儿童胃灼热，成人发展为食管狭窄和食物嵌塞。虽然最初 被认为是罕见的，发病率和患病率急剧上升，在过去的十年中， 迅速成为上消化道疾病的主要原因。尽管人们越来越了解 目前还无法确定个别患者发生EoE的原因。这是令人沮丧 对病人和医生都是一样的。EoE被认为是一种免疫/过敏原介导的疾病， 流行病学研究支持一个主要的环境病因。环境风险因素 没有在EoE中进行广泛的研究，之前的研究，包括我们自己的小组，都受到了原油的限制。 暴露评估、回忆偏倚、无法评估胎儿生物标志物和缺乏机制 认识我们的目标是通过使用一种创新的方法来精确测量 乳牙（乳牙或“婴儿”）的早期暴露可能与EoE的发育有关。的 特别令人感兴趣的是生命早期抗生素暴露以及母乳喂养的持续时间和强度（这可能是 来源于牙齿中的钡水平）。抗生素暴露增加和母乳喂养减少， 与特应性疾病的风险有关。测量牙齿中选定的环境暴露从未被应用过 但我们已经证明了这种方法的可行性。这一评估，连同使用 新的细胞和分子技术，阐明这些早期的影响机制， 生活暴露，有可能大大提高我们对EoE发病机制的理解。我们 一种假说认为，与生命早期暴露相关的EoE风险主要是由于食管损伤， 上皮屏障，遗传易感性将与暴露相互作用以改变风险。具体 目的是1）确定早期抗生素暴露与EoE之间的关系; 2）确定是否 母乳喂养与EoE相关，并评估CAPN 14的易感基因型是否改变了 母乳喂养与EoE之间的关系; 3）确定功能意义和机制 早期暴露对食管上皮结构和屏障功能的影响。为了实现这些目标，我们 将进行一项病例对照研究，以描述时间暴露的特征，同时将进行机械性 分析。这项创新的，假设驱动的，严格设计的研究将导致强大的和公正的 结果它将由一个多学科小组进行，该小组在EoE，流行病学， 临床/转化/实验室研究和暴露科学。其结果将对 了解EoE病因，并通过潜在地确定疾病预防的机会， 导致新的治疗选择的发展。