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)...