EoE is a newly recognized chronic, antigen driven allergic disease that causes tissue remodeling. Esophageal remodeling includes fibrosis and smooth muscle hypertrophy/dysfunction that leads to esophageal rigidity and dysmotility. Clinical symptoms include vomiting, poor growth, dysphagia, food impactions, and strictures. My patient oriented research (POR) program focuses on elucidating the mechanisms and clinical impacts of esophageal remodeling in children. Herein I propose to become an outstanding POR mentor to a diverse group of undergraduate/graduate students, postdoctoral fellows, and junior faculty trainees from multiple disciplines and to continue and extend my research to understanding EoE as a disease of both inflammation and ?mechanotransduction?. In the Research Plan, I test 3 hypotheses on the fundamental mechanisms of EoE. The first is a potentially paradigm shifting central hypothesis that a rigid matrix alters the function of esophageal fibroblasts and smooth muscle cells to propagate EoE together with, and independently of, inflammation. This has the clinical implication that there is a pressing, unmet clinical need for therapies that target inflammation- independent remodeling. The second hypothesis, an extension of my current POR, is that the adherens junction protein, E-cadherin, is pivotal in the loss of esophageal epithelial cell barrier function and that super resolution microscopy is a cutting-edge tool that will aid our understanding of the interaction between barrier function and E-cadherin localization at the nanometer level.
The third aim i s to evaluate gender differences in EoE severity with the hypothesis that male fibroblasts are intrinsically more biased to esophageal inflammation and remodeling. Together with my collaborators and our co-mentees, I have developed and utilized innovative primary human models that transition from single cells and intact multicellular and functional ex vivo human mucosal platforms to an in vivo analyses of esophageal rigidity and motility in children. With our large, well- phenotyped EoE population, we are able to continuously translate our findings back to the patient. I have involved mentees in each of my aims, developed a formal plan to train junior investigators in the lab, clinic and career path, created a formal mentoring plan and team for my mentees and myself, and integrated the unique resources at UCSD including the CTSA funded Clinical and Translational Research Institute. I have a strong record of funded POR and training mentees but require the protected time and further education to become the inspiring mentor I envision. This is an important goal for sustaining research and creating a legacy of investigators in eosinophilic gastrointestinal disorders (EGIDs). My past and current group of mentees are from Allergy/Immunology, Gastroenterology, and Bioengineering, all of whom are dedicated to, and united by, the singular goal of unraveling mechanisms of EGIDs and bringing the findings back to the patient. The combination of a multidisciplinary mentee team, an outstanding research and institutional environment, and a strong mentoring plan are key to the success of this proposal.

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, strictures, and food impactions caused by fibrosis and smooth muscle changes referred to as tissue remodeling. I have a strong foundation of mentoring trainees and conducting patient oriented research (POR). I proposes to integrate funded research and strong pool of junior investigators from multiple disciplines to become an outstanding POR mentor and expand my current EoE remodeling research to unanswered questions of how a rigid matrix alters structural cell function, gender differences, and mechanisms of epithelial barrier dysfunction in EoE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AI135034-02
Application #
9613216
Study Section
Allergy, Immunology, and Transplantation Research Committee (AITC)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2017-12-12
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
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
Doshi, Ashmi; Khamishon, Rebecca; Rawson, Renee et al. (2018) IL-9 Alters Epithelial Barrier and E-cadherin in Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr :
Spergel, Jonathan; Aceves, Seema S (2018) Allergic components of eosinophilic esophagitis. J Allergy Clin Immunol 142:1-8
Nhu, Quan M; Aceves, Seema S (2017) Tissue Remodeling in Chronic Eosinophilic Esophageal Inflammation: Parallels in Asthma and Therapeutic Perspectives. Front Med (Lausanne) 4:128