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.

项目摘要 本研究的长期目标是阐明嗜酸性食管炎的遗传学和免疫学特征 （EoE）。EoE是一种新出现的慢性疾病，通常始于儿童期并持续到成年期， 然而，目前还没有FDA批准的治疗方法。理解这一 这一主题具有重要的意义，因为它阐明了这种疾病的基本遗传学和免疫学特征。 疾病有可能产生改进的诊断和治疗。这一提议的核心假设是， 全基因组关联研究（GWAS）的询问，随后是遗传和生物学验证，将揭示 参与疾病病理学的关键过程，重点是适应性免疫和先天免疫的界面。 这一假设的基本原理是基于我们先前的研究，包括已经确定疾病的初始GWAS。 染色体2 p23和5 q22的易感性。越来越多的证据表明，这两个基因座上的致病基因 分别是CAPN 14（钙蛋白酶14）和TSLP（胸腺基质淋巴细胞生成素）。这些发现转移了人们的注意力， 从原发性嗜酸性粒细胞缺陷到上皮反应是EoE发病的原因。机械论 研究已经确定CAPN 14有助于受损的上皮屏障功能，并且TSLP促进 与IL-5和IL-13过度产生相关的适应性2型T细胞免疫。CAPN 14位于接口处 先天性和适应性免疫，因为它是由食管上皮组成型表达;然而，它也是 由IL-13显著诱导，可能来源于食物抗原活化的Th 2细胞。除了这两个基因 基因座（2 p23，5 q22），GWAS还涉及许多其他提示基因座，其中11个最近已被发现 使用定制设计的Illumina SNP阵列方法初步暗示， 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/或基因组途径仍然存在。 仍然很不清楚。在这里，我们将测试相关的和关键的假设，即GWAS审讯，其次是 通过遗传学和生物学验证，将揭示疾病的病因。我们将通过3来检验这个中心假设 互补的目的是使用创新的方法，结合联合收割机遗传和生物学研究。在目标1中，我们 关注一个主要的GWAS导联CAPN 14。我们将测试CAPN 14是一种重要的调节因子的假设。 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。我们 将确定其结合伙伴和潜在的底物和CAPN 14缺陷的后果， 食管上皮细胞和CAPN 14转基因过表达。在目标2中，我们将检验假设 GWAS分析的其他EoE队列的荟萃分析将细化涉及 基因座/基因并识别新的变体。在目标3中，我们将询问疾病相关的单核苷酸 通过创新的遗传学、染色质作图、转录组学表达 分析和功能生物学研究，以确定遗传变异的相关性并鉴定致病基因。