This is an A2 application that uses genetically engineered mice to evaluate the regulation of parietal cell function and mechanisms involved in the development of autoimmune gastritis (AIG). The analysis is focused on the Ctox7 transgenic mouse model, which was developed in the previous funding period. Ctox transgenics have enhanced acid secretion resulting from increased parietal cell cAMP. As the mice age they develop atrophic gastritis associated with the production of anti-parietal cell antibodies. The spontaneous development of autoimmunity defines a new experimental model for AIG, which is the focus of this application. We test the following overriding hypothesis: Hyperstimulation of the parietal cell due to chronic high cAMP leads to inflammation, which results in the development of AIG and the destruction of parietal cells and eventual gastric mucosal transformation.
Three specific aims are directed to different aspects of the proposed mechanism.
Aim 1 will focus on the significance of the cAMP hyperstimulation in regard to parietal cell function and death. Our preliminary results show increased TUNEL staining in the glandular compartment suggesting an apoptotic mechanism for the atrophy. We will test whether increased parietal cell cAMP predisposes the parietal cell to sensitivity to cytokine-induced cell death. We will also examine changes in morphology and gene expression resulting from increased cAMP to further understand the significance of this critical parietal cell signaling regulator.
Aim 2 will focus on the inflammatory response and test the hypothesis that AIG is associated with a Th1 immune response dependent on the cytokine interferon-7 (IFN-y). Cellular infiltrates will be characterized by FACS analysis and cytokine production in stomach and spenocytes will be analyzed. Preliminary data shows Ctox7 transgenics have increased IFN-y expression. Analyzing Ctox7 transgenics on an IFN-y deficient background will test cytokine dependency.
Aim 3 will test the strain-dependency of AIG and whether inflammation induced by environmental pathogens can enhance the development of AIG. Spontaneous development of autoimmunity in a C57BL/6 strain is unique to the Ctox7 model of autoimmune gastritis. We will also test Ctox7 on a Balb/c background, which is the permissive strain background for other models of AIG.
This aim will also examine the importance of environmental pathogens by analysis of Helicobacter infected and germ-free mice. These experiments will compare the Ctox7 model to the previously characterized mouse thymectomy model of AIG. Chronic atrophic gastritis, and AIG leading to pernicious anemia are significant human health concerns. This project will use a new experimental mouse model of AIG to examine mechanisms leading to the development of autoimmune disease in the stomach. These studies will further our understanding of the significance of parietal cell stimulation and Helicobacter infection on the development of gastric inflammation, which is associated with the development of stomach cancer. ? ? ? ? ?
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