Eosinophilic esophagitis (EoE) is a recently characterized disease that has rapidly increased in incidence over the past decade. It affects people at all ages with a preference in children and adults in their 30-40s. The etiology of EoE has been linked to allergen/immune reactions with characterized high levels of cytokines including IL-13. Prolonged inflammation leads to tissue remodeling including hyperplasia of basal progenitor cell, subepithelial fibrosis and stricture of the esophagus. Although current therapies (e.g. topical steroid application) are effective in reducing inflammation, their effects n existing tissue remodeling are largely unknown. Therefore a better understanding of the pathobiology of the disease is necessitated for deriving novel effective treatment. Multiple lines of evidence support that IL-13 plays important roles in the initiation of EoE and subsequent tissue remodeling. Genetic removal of Stat6, downstream target of IL-13 alleviates basal cell hyperplasia. However, how IL-13 regulates basal progenitor cells during tissue remodeling remains unexplored. We previous established that Bone morphogenetic protein (Bmp) signaling regulates the differentiation of basal progenitor cells in the developing esophagus. Significantly, our preliminary data suggest Bmp signaling is diminished in EoE mouse models and human biopsies. We therefore propose to determine how Bmp signaling is altered and participates in the pathological progression of EoE. Our central hypothesis is that IL-13 promotes basal cell hyperplasia through the inhibition of Bmp signaling-mediated differentiation during EoE tissue remodeling. We will test these three specific aims: (1) To test the hypothesis that suppressed Bmp signaling promotes basal cell hyperplasia during EoE tissue remodeling. (2) To test the hypothesis that IL-13 promotes basal cell hyperplasia by upregulating the Bmp inhibitor Follistatin. (3) To target Follistatin with novel compounds for attenuating basal cell hyperplasia. This project is expected to provide novel genetic and molecular mechanisms of basal progenitor cell differentiation. The insights gained through studying Bmp signaling in EoE animal models and human biopsies will lay an important foundation for translating these findings into the clinic.

Public Health Relevance

Eosinophilic esophagitis (EoE) is a growing medical problem affecting people at all ages with a preference for children. Despite its association with allergen/immune reactions, there is a poor understanding of molecular basis underlying disease progression. Here we aim to determine the contribution of epithelial stem/progenitor cells to EoE pathogenesis, and the proposal will provide novel insight into fundamental mechanisms with broad scientific and clinical implications.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK100342-01
Application #
8614562
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627