Eosinophilic esophagitis (EoE) is a chronic food antigen driven allergic disease of increasing prevalence (5.6/10,000) that requires endoscopy with biopsy for its diagnosis and management and creates a large healthcare burden with an estimated annual cost of up to $1 billion. Complications are caused by tissue remodeling that includes fibrosis and smooth muscle hypertrophy leading to a rigid, poorly motile, narrowed esophagus with food impactions and strictures. Children have pain, poor growth, dysphagia and persistent disease, underscoring a pressing need to understand the mechanisms of disease complications to effectively treat EoE, decrease the healthcare burden, and improve quality of life. We have shown that tissue remodeling begins early in childhood, responds variably to anti-inflammatory therapy, and that transforming growth factor beta-1 (TGF?1) is integral to pediatric EoE. TGF?1induces smooth muscle contraction via the calcium channel regulatory protein, phospholamban (PLN) and recently we have found that it induces epithelial expression of the pro-fibrotic factor plasminogen activator inhibitor-1 (PAI-1). The current disease paradigm is that inflammation is the singular trigger for remodeling. However, our novel preliminary data support the paradigm shifting central hypothesis that a rigid matrix drives structural cell dysfunction to promote EoE remodeling by inducing smooth muscle hypertrophy, fibroblast production of extracellular matrix proteins, and epithelial proliferation. We propose 3 independent specific aims to: 1) dissect the role of PLN in rigid matrix-induced smooth muscle hypertrophy and contraction, 2) understand the effects of rigid matrix on EoE and normal fibroblast gene expression and delineate whether EoE matrix is sufficient to alter normal fibroblast function, and 3) to simultaneously measure pediatric esophageal rigidity and motility using a new application of endoscopic functional luminal imaging probe technology, to delineate if epithelial cell response to TGF?1is increased by rigid matrix, and to understand if epithelial PAI-1 serves as a marker of esophageal function. In order to test these hypotheses we will utilize novel human model systems including precisely bioengineered silicone substrates with primary cells and new functional platforms including smooth muscle co-cultured esophageal organoids, ex vivo intact human esophageal mucosal strips and muscle bundles as well as transgenic cells. We have assembled a strong and unique team of investigators with expertise in translational EoE, cell biology, physiology, and esophageal motility and combined this with our large well-phenotyped EoE pediatric population. These studies are innovative in concept and design and will help to dissect the fundamental biology of the novel and central concept that a rigid matrix contributes to EoE pathogenesis.

Public Health Relevance

EoE is an allergic disease of increasing prevalence that requires repeated esophageal biopsy and is treated with anti-inflammatory therapy to control the complications of esophageal rigidity with stricture and food impactions caused by fibrosis and smooth muscle changes referred to as tissue remodeling. However, not all subjects respond to anti-inflammatory therapy and complications can occur despite therapy. This proposal suggests the novel hypothesis that smooth muscle and fibroblast function is regulated by a rigid matrix and aims to dissect the mechanisms by which a stiff matrix alters esophageal cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092135-08
Application #
9519791
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Minnicozzi, Michael
Project Start
2011-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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