Genetic and Immunological Dissection of Eosinophilic Esophagitis

嗜酸性粒细胞性食管炎的遗传学和免疫学剖析

• 批准号: 10364802
• 负责人: Marc E. Rothenberg
• 金额: $ 65.86万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364802
• 关键词: 2p23; Adult; Allergic; Binding; Biological; Biological Models; Biological Products; CD4 Positive T Lymphocytes; Calpain; Cell physiology; Childhood; Chromatin; Chromosomes; Chronic; Chronic Disease; Clinical; Cohort Analysis; Custom; Data; Databases; Defect; Deglutition Disorders; Diagnostic; Disease; Disease susceptibility; Dissection; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Esophageal Diseases; Esophageal Tissue; Esophagus; Evaluation; Expression Profiling; Extracellular Space; FDA approved; Food; Fostering; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Goals; Grant; Health; Heritability; Histologic; Human; Hyperplasia; Immune response; Immunity; Immunologics; Impairment; In Vitro; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Interleukin-5; Lead; Longitudinal Studies; Lung; Mediating; Meta-Analysis; Mission; Morbidity - disease rate; Mus; Natural Immunity; Pain; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Predisposition; Process; Proteomics; Public Health; Research; Role; Series; Single Nucleotide Polymorphism; Skin; Suggestion; Susceptibility Gene; System; T-Lymphocyte; TSLP gene; Testing; Th2 Cells; Therapeutic; Transgenic Organisms; United States National Institutes of Health; Validation; Variant; Vomiting; adaptive immunity; advanced disease; base; causal variant; design; desmoglein 1; eosinophil; follow-up; food antigen; gene product; genetic approach; genetic association; genetic variant; genome wide association study; genome-wide; genomic locus; improved; in vivo Model; innovation; novel; overexpression; programs; response; risk variant; targeted agent; tool; transcriptomics

Project Summary This study's long-term goal is to elucidate the genetic and immunologic features of Eosinophilic Esophagitis (EoE). EoE is an emerging chronic disease that often starts in childhood and continues into adulthood and is associated with substantial morbidity, yet there are currently no FDA-approved therapies. Understanding this subject has significant implications as elucidating the fundamental genetic and immunologic features of the disease has potential to yield improved diagnostics and therapies. The central hypothesis of this proposal is that genome-wide association study (GWAS) interrogation, followed by genetic and biological validation, will uncover key processes involved in disease pathoetiology with a focus on the interface of adaptive and innate immunity. The rationale for this hypothesis is based on our prior studies, including initial GWAS that have identified disease susceptibility at chromosomes 2p23 and 5q22. Evidence is accumulating that the causal genes at these 2 loci are CAPN14 (calpain 14) and TSLP (thymic stromal lymphopoietin), respectively. These findings shift the focus from primary eosinophil defects to epithelial responses as being causal of EoE pathogenesis. Mechanistic studies have established that CAPN14 contributes to impaired epithelial barrier function and that TSLP promotes adaptive type 2 T cell immunity associated with overproduction of IL-5 and IL-13. CAPN14 sits at the interface of innate and adaptive immunity, as it is constitutively expressed by esophageal epithelium; however, it is also markedly induced by IL-13, likely derived from food antigen–activated Th2 cells. In addition to these 2 genetic loci (2p23, 5q22), GWAS have implicated numerous other suggestive loci, of which 11 have been recently preliminarily implicated using a custom-designed Illumina SNP array approach followed by preliminary functional analyses. Despite these advances, the causal gene variants and/or genomic pathways for EoE pathogenesis remain largely unclear. Herein, we will test the relevant and key hypothesis that GWAS interrogation, followed by genetic and biological validation, will uncover disease pathoetiology. We will test this central hypothesis via 3 complimentary aims using innovative approaches that combine genetic and biological studies. In Aim 1, we will focus on a primary GWAS lead, CAPN14. We will test the hypothesis that CAPN14 is an essential regulator of cellular junctions and barrier integrity and contributes to IL-13–induced, EoE-related epithelial responses. We will identify its binding partners and potential substrates and the consequences of CAPN14 deficiency in esophageal epithelial cells and CAPN14 transgenic overexpression in mice. In Aim 2, we will test the hypothesis that meta-analysis of additional EoE cohorts analyzed by GWAS will refine the involvement of implicated loci/genes and identify new variants. In Aim 3, we will interrogate disease-associated single-nucloeotide polymorphisms (SNPs) by a combination of innovative genetic, chromatin mapping, transcriptomic expression profiling, and functional biological studies to establish relevance of the genetic variants and identify causal genes.

项目概要 本研究的长期目标是阐明嗜酸性食管炎的遗传和免疫学特征 (EoE) 是一种新出现的慢性疾病，通常始于儿童期并持续至成年期。 与大量发病率相关，但目前尚无 FDA 批准的治疗方法。 该课题对于阐明该疾病的基本遗传和免疫学特征具有重要意义。 该提案的中心假设是，该疾病有可能改善诊断和治疗。 全基因组关联研究（GWAS）询问，随后进行遗传和生物学验证，将揭示 疾病病理学涉及的关键过程，重点是适应和先天免疫的界面。 这一假设的基本原理基于我们之前的研究，包括已确定疾病的初始 GWAS 染色体 2p23 和 5q22 的易感性 越来越多的证据表明这 2 个基因座的致病基因。 分别是 CAPN14（钙蛋白酶 14）和 TSLP（胸腺基质淋巴细胞生成素），这些发现转移了焦点。 从原发性嗜酸性粒细胞缺陷到上皮反应是 EoE 发病机制的原因。 研究已证实 CAPN14 会导致上皮屏障功能受损，而 TSLP 会促进 与 IL-5 和 IL-13 过量产生相关的适应性 2 型 T 细胞免疫位于界面处。 先天性和适应性免疫，因为它是由食管上皮组成性表达的；然而，它也是 除了这 2 种遗传细胞外，IL-13 明显诱导，可能源自食物抗原激活的 Th2 细胞。 基因座 (2p23, 5q22)，GWAS 涉及许多其他暗示性基因座，其中 11 个最近已被 初步暗示使用定制设计的 Illumina SNP 阵列方法，然后进行初步功能分析 尽管取得了这些进展，但 EoE 发病机制的致病基因变异和/或基因组途径。 在此，我们将检验 GWAS 审讯所遵循的相关且关键的假设。 通过遗传和生物学验证，将揭示疾病病理学，我们将通过 3 检验这一中心假设。 在目标 1 中，我们将使用结合遗传和生物学研究的创新方法来实现互补目标。 我们将重点关注主要 GWAS 线索 CAPN14，我们将检验 CAPN14 是 GWAS 的重要调节因子的假设。 细胞连接和屏障完整性，并有助于 IL-13 诱导的 EoE 相关上皮反应。 将确定其结合伙伴和潜在底物以及 CAPN14 缺乏的后果 食管上皮细胞和 CAPN14 转基因小鼠的过度表达 在目标 2 中，我们将检验这一假设。 通过 GWAS 分析的其他 EoE 队列的荟萃分析将完善相关参与 在目标 3 中，我们将探究与疾病相关的单核苷酸。 通过创新遗传、染色质作图、转录组表达相结合的多态性 (SNP) 分析和功能生物学研究，以确定遗传变异的相关性并识别因果基因。