Gastric cancer is now the third most common diagnosed cancer of humans. It is the second most common cause of cancer-related deaths worldwide, only surpassed by smoking-related lung cancer. Infection with the bacterium Helicobacter pylori is causally associated with gastritis and peptic ulcer, as well as gastric adenocarcinoma and gastric lymphoma of mucosa-associated lymphoid tissue (MALT). Remarkably, a single bacterial protein called CagA is thought to play the principal role in the transition from simple inflammation to ulcer disease and adenocarcinoma. However, we don't understand why the vast majority of individuals infected by H. pylori remain free of serious disease even though often infected for a lifetime. ? ? Our work focuses on understanding what host factors, together with the genetic make-up of the infecting H. pylori, contribute to whether there is a relatively benign host-microbial relationship or the more devastating outcome of duodenal ulcer or gastric cancer. Using contemporary tools of bacterial genetics, molecular biology, cell biology and functional genomics, our proposed research will try to answer the following questions. How does Helicobacter pylori breach the gastric barrier to establish itself and to persist in the host? How does the organism manipulate the host immune system to persist for a lifetime? What is the failure of a natural infection to afford any immunity at all? Why, after we eradicate the microbe by antibiotic treatment, is re-infection even more deleterious for the host? What are the underlying features of the malignant transformation that are so intimately associated with the phosphorylation of the bacterial protein CagA? Our experimental approach to these questions makes use of animal models of infection and the study of the host response to infection, as well as what modifications of the genetic structure of the bacterium have on infectivity and it's ability to induce malignancy. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092229-07
Application #
7224109
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2001-07-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
7
Fiscal Year
2007
Total Cost
$283,208
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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