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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01DK097144-04
Application #
8852607
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2012-09-15
Project End
2016-05-31
Budget Start
2014-12-29
Budget End
2015-05-31
Support Year
4
Fiscal Year
2015
Total Cost
$83,700
Indirect Cost
$6,200
Name
Montana State University - Bozeman
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717