PROJECT SUMMARY Esophageal diseases are extremely common with over a million outpatient clinic visits for dysphagia a year, 20% of the population suffering with gastroesophageal reflux disease and approximately 50,000 emergent endoscopies being performed a year for food impactions. Symptoms focused on dysphagia, chest pain, regurgitation and fear of choking dramatically impact quality of life and aspiration and malnutrition are associated with significant mortality. Central to esophageal disease pathogenesis is abnormal bolus transport and this function is dependent on a delicate mechanical interplay as the esophagus must accommodate a large volume in a short time and propel the bolus down the esophagus in a low-pressure state. Given this delicate balance, even small changes in esophageal wall distensibility can have dramatic effects on bolus transport and the strain/stress relationship of the esophageal wall. To date, there has been very little investigation into these important mechanical processes as most of the emphasis has been on peristalsis and contractile vigor. Using novel techniques developed in our lab focused on high-resolution impedance, our team has been able to show that the mechanical properties of the esophageal wall and the response to volume distention are important in esophageal disease pathogenesis. Using the functional lumen imaging probe (FLIP) and refining this technique into FLIP-panometry, we were able to determine new metrics that define wall distensibility in eosinophilic esophagitis, achalasia and non-obstructive dysphagia. Additionally, we defined a new motor pattern that was directly stimulated by distention and likely represents a secondary peristaltic like response in the form of repetitive antegrade contractions (RACs). Further work focused on RACs support that this response has important functional and clinical relevance in esophageal acid clearance and bolus transport in dysphagia. Given this preliminary data, we have developed a program project grant (PPG) focused on “Disordered Tissue Biomechanics as a Driver of Esophageal Diseases”. In order to fully understand this pathogenic mechanism, we have brought together a group of investigators with varying expertise to develop a comprehensive model of disease activity using a 4 pronged attack. Project 1 will determine the triggers and molecular mechanisms behind abnormal wall distensibility and Project 2 will study the effect of esophageal wall distensibility on altering the response to volumetric distention focused on its effect on bolus transport. Project 3 will utilize direct measures of tissue material properties and physiologic data from Project 2 to develop in-silico models of esophageal transport to both test the hypotheses derived in Projects 1 and 2 and reverse engineer hybrid diagnostics that can determine the actual mechanics behind the abnormal function uncovered by FLIP and manometry. Last, Project 4 will determine the role of central mediated cognitive processes on symptoms and as an overarching goal develop a complex model that will incorporate physiologic biomarkers, measures of mechanical properties of the esophageal wall with psychological mediators of symptom generation.

PROJECT NARRATIVE Esophageal disease is associated with a significant reduction in quality of life that is directly related to symptoms of dysphagia, chest pain, regurgitation, and choking. There is also secondary morbidity and mortality associated with aspiration and malnutrition. This program project grant assembles a team of investigators from a wide range of disciplines to study how disease states alter the structure and mechanical properties of the esophagus resulting in compromised function. We will be using animal models of scleroderma and eosinophilic esophagitis, human physiologic studies, mathematical models, computer simulations, and psychometric analysis to develop an array of tools aimed at improving the management of esophageal disease.