Helicobacter pylori is one of the world's most widespread human pathogens, infecting more than 50% of the population. This pathogen is the major contributor to gastric cancer, which is the second leading cause of cancer deaths in the world. H. pylori induces macrophage migration inhibitory factor (MIF) production from gastric epithelial cells, and MIF production is an important factor in many cancers. A receptor for MIF is CD74, which I have shown to be highly expressed both in vivo and in vitro, and is upregulated by H. pylori. CD74 has also been shown to be highly expressed in a variety of cancers and is being studied as a therapeutic target in both cancer and immunologic diseases. The finding that H. pylori upregulates CD74, along with the ability of H. pylori to induce MIF, and the role MIF plays promoting carcinogenesis led to the hypothesis that: Helicobacter pylori induces gastric epithelial cell production of MIF, which binds to surface-expressed CD74 resulting in pro-carcinogenic signaling.
The specific aims to address this hypothesis are:
AIM 1. To characterize the mechanisms involved in H. pylori-induced gastric epithelial cell MIF production where the kinetics, the bacterial factors, and the signaling involved in MIF production will be assessed.
AIM 2. To determine the role of CD74 in the interaction of MIF with gastric epithelial cells and whether this binding induces signaling events associated with H. pylori infection. The role of CD74 as the receptor for MIF on gastric epithelial cells will be examined along with the presence of any other receptors MIF may utilize. The ability of MIF-bound CD74 to modulate signaling typically seen during H. pylori infection will also be investigated.
AIM 3. To determine the role of MIF binding to CD74 on gastric epithelial cell pro-carcinogenic signaling and proliferation. The kinetics of proliferation and apoptosis will be compared with virulent bacteria, strains with deleted cag, anti-CD74 blocking antibodies, and anti-MIF neutralizing antibodies. The effects of MIF on cell cycle kinetics will be examined. These studies will provide valuable insight into cell signaling and responses that are crucial in both inflammation and the development of gastric cancer.
