The applicant's career goal is to become an independent scientist in the field of human mucosal immunology with a focus on the role of dendritic cells (DCs) in H. pylori infection. To meet this goal, the applicant proposes a career development plan that will allow her to gain additional experience in mucosal DC research plus training in autoimmunity research, cancer biology, proteomics methods, grant writing and leadership skills through practical experience, formal course work and mentoring. A highly accomplished team of investigators will oversee the applicant's career development and provide expertise on individual aspects of the research project. The research component of this project seeks to elucidate mechanisms by which DCs contribute to the long-term sequelae of H. pylori gastritis, i.e., gastric atrophy and neoplasia. The overall hypothesis is that cross-talk between gastric epithelial cells and underlying lamina propria DCs contributes profoundly to the regulation of disease progression in human H. pylori infection. This hypothesis will be tested with the following Specific Aims: (1) Determine whether human gastric epithelial cells regulate gastric DC activation and DC function, including DC-induced T cell proliferation, in early H. pylori infection;(2) Determine whether defective antigen-presenting cell clearance of apoptotic epithelial cells in H. pylori gastritis contributes to chronic inflammation and gastric autoimmunit;and (3) Determine whether gastric DC secretion of IL-8 and MIF promotes epithelial cell proliferation through the CXCR2-EGF-R axis in H. pylori gastritis.
Specific Aims 1 and 2 will address the effects of live, apoptotic and necrotic epithelial cells on DC function in the context f early or chronic H. pylori infection, whereas Specific Aim 3 will focus on the effects of DC-derived signals on gastric epithelial cell proliferation, thereby completing the cross-talk circle. We anticipate that DCs and epithelial cells in chronic H. pylori infection cause mutual activation leading to non-resolving inflammation and dysregulation of epithelial cell turnover, a key element in the progression of chronic H. pylori inflammation to gastric adenocarcinoma. This project will greatly enhance our understanding of chronic disease mechanisms in human H. pylori infection and will also provide critical training for Dr. Bimczok's development as an independent scientist.
Gastric adenocarcinoma, the second leading cause of cancer related mortality world wide, is a long term consequence of chronic inflammation caused by H. pylori infection. Here, we will investigate whether interactions between gastric epithelial cells and gastric dendritic cells contribute to non-resolving inflammation and disease progression to gastric cancer.
|Bimczok, D; Kao, J Y; Zhang, M et al. (2015) Human gastric epithelial cells contribute to gastric immune regulation by providing retinoic acid to dendritic cells. Mucosal Immunol 8:533-44|
|Das, Soumita; Sarkar, Arup; Ryan, Kieran A et al. (2014) Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells. FASEB J 28:2214-24|
|Smith, Phillip D; Shimamura, Masako; Musgrove, Lois C et al. (2014) Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. J Immunol 193:5604-12|
|Bimczok, Diane; Smythies, Lesley E; Waites, Ken B et al. (2013) Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immunol 190:6626-34|