Chronic inflammation in the stomach (gastritis) is usually associated with Helicobacter pylori, but may occur from bacterial overgrowth because of hypochlorhydria. Chronic gastritis also results in initial increase then loss of parietal cells over time (chronic atrophic gastritis). A recurring theme is that disruption of parietal cell function eventually results in fewer parietal cells followed by an expansion of the mucous and undifferentiated cell types in the stomach. Interestingly, destruction of the parietal cell through ectopic expression of toxins has also been reported to generate the same phenotype. In some instances, these phenotypic alterations progress to the point where mucous cell types emerge, a subset of which express intestine-specific genes (intestinal metaplasia). Intestinal metaplasia is a condition that predisposes the gastric mucosa to cancer. Central to initiating these important alterations are changes in the parietal cell population. In this proposal, we hypothesize that an important trigger altering the normal phenotypic pattern of gastric epithelial cells is inflammation generated from bacterial colonization. The primary goal of this proposal is to understand how components of a bacterial infection trigger parietal cell atrophy and subsequently pre-neoplastic changes. The preliminary results show that both CagA and INF( alter gastric architecture. First, the experiments proposed use a transgenic mouse model expressing CagA (Aim 1) or treatment of mice with pro-inflammatory cytokines (Aim 2) to alter parietal and mucous cell populations. Second, in vitro studies in primary parietal and mucous cells cultures, will be used to dissect the signaling pathways activated (Aim 3) and will study the target proteins regulated during the transformation of the mucosa from chronic atrophy to dysplasia (Aim 4). We will examine whether Sonic hedgehog expressed primarily in parietal cells may be lost during parietal cell atrophy and contribute to the increase in mucosal proliferation and subsequently transformation. These studies will further our understanding of how corpus atrophy predisposes the gastric mucosa to neoplastic transformation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061410-02
Application #
6698037
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
May, Michael K
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$283,343
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kang, Weiqun; Saqui-Salces, Milena; Zavros, Yana et al. (2008) Induction of follistatin precedes gastric transformation in gastrin deficient mice. Biochem Biophys Res Commun 376:573-7
Gumucio, D L; Fagoonee, S; Qiao, X T et al. (2008) Tissue stem cells and cancer stem cells: potential implications for gastric cancer. Panminerva Med 50:65-71
Merchant, Juanita L (2008) What lurks beneath: IL-11, via Stat3, promotes inflammation-associated gastric tumorigenesis. J Clin Invest 118:1628-31
Zavros, Yana; Waghray, Meghna; Tessier, Arthur et al. (2007) Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation. J Biol Chem 282:33265-74
Merchant, Juanita L (2007) Tales from the crypts: regulatory peptides and cytokines in gastrointestinal homeostasis and disease. J Clin Invest 117:6-12
Shiotani, Akiko; Uedo, Noriya; Iishi, Hiroyasu et al. (2007) Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer 121:1182-9
Kao, John Y; Rathinavelu, Sivaprakash; Eaton, Kathryn A et al. (2006) Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: a mechanism of ineffective host defense. Am J Physiol Gastrointest Liver Physiol 291:G73-81
Shiotani, A; Iishi, H; Uedo, N et al. (2006) Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression. Aliment Pharmacol Ther 24 Suppl 4:71-80
Kang, Weiqun; Rathinavelu, Sivaprakash; Samuelson, Linda C et al. (2005) Interferon gamma induction of gastric mucous neck cell hypertrophy. Lab Invest 85:702-15
Rathinavelu, Sivaprakash; Kao, John Y; Zavros, Yana et al. (2005) Helicobacter pylori outer membrane protein 18 (Hp1125) induces dendritic cell maturation and function. Helicobacter 10:424-32

Showing the most recent 10 out of 16 publications