The overarching hypothesis of this program project grant (PPG) is focused on the role of disordered esophageal wall mechanics in the pathogenesis of esophageal diseases. Given that the primary purpose of the esophagus is to transport bolus, a more in depth understanding of fluid dynamics and the strain/stress relationship of the esophageal wall is crucial to understanding esophageal diseases. Bolus transport abnormalities are the cause of most esophageal symptoms and complications and this process is highly dependent on the mechanics of the esophageal wall. Esophageal peristalsis is only a small component of the bolus transport mechanism in the esophagus and the interplay between bolus accommodation and how it is propelled through the non-contracting esophagus is likely more important than reduced peristaltic vigor. The bolus delivered from the oropharynx during swallowing must be accommodated and even minor perturbations in the mechanical state of the esophageal wall can have dramatic effects on strain/stress relationship. Thus, we have proposed a PPG focused on developing a comprehensive understanding of how wall distensibility can alter bolus transport and symptoms. Project 1 will focus on determining the role of IKK?/NF?B in promoting reduced distensibility in eosinophilic esophagitis (EoE) and assessing the role of STAT 3 in promoting atrophy and fibrosis in scleroderma. Human studies will be performed in well-defined phenotypes of EoE and scleroderma and the Biorepository and Tissue Material Characterization CORE (CORE C) will be crucial in collecting and preparing the specimens for these studies. Additionally, we will also determine whether the material properties measured in the Tissue Material Characterization sub-CORE are correlated with activity of the targets defined during the animal studies in Project 1. CORE C will also be extremely important in providing crucial information for the mathematical models and Virtual Disease Landscape as the material properties in normal subjects and various disease states will be important inputs into the models. The specimens used for the model will be comprised of micro- and macros-scale measurements and tissue will be obtained through endoscopic biopsies and discarded tissue in post-surgery patients. Although the primary role for CORE C will be to support Project 1 and Project 3 through the models developed within the Biophysiologic Modeling Core (CORE B), Projects 2 and 4 will benefit indirectly from CORE C as the data collected will generate and refine the mechanical biomarkers in the models to predict bolus transport and symptom severity.
The current program project grant will focus on the role of abnormal esophageal wall mechanics in esophageal disease and the molecular mechanisms that lead to abnormal wall distensibility. The goal of CORE C will be to facilitate collection and storage of tissue and blood from well-defined clinical phenotypes to study how specific molecular triggers and signals modulate wall distensibility. Additionally, CORE C will also help characterize the micro- and macro-scale tissue properties from the phenotypes to help better understand the pathogenesis of abnormal wall mechanics and to inform the virtual disease models developed in CORE B.