Sphingolipid mediators, are involved in complex cell signaling pathways that regulate cell growth, apoptosis and differentiation. Dietary sphingomyelin is avidly metabolized in the intestinal tract into polar metabolites such as sphingosine and sphingosine 1-phosphate (S1P). Our laboratory defined the first G protein-coupled receptor for SIP and characterized its receptor-dependent actions. Merrill and colleagues have shown that dietary sphingomyelin is chemopreventive in carcinogen-induced and tumor-suppressor gene deleted (ApcMin/+) models of intestinal tumorigenesis. In addition, increased intake of sphingolipid-rlch diets (such as soy), which raises intracellular sphingosine levels is associated with reduced Incidence of intestinal cancer. These data suggest that sphingolipid mediators are potent modulators of intestinal tumorigenesis. This proposal is based on the hypothesis that sphingosine kinase is a key regulatory enzyme that facilitates intestinal tumorigenesis by suppressing intracellular levels of tumor suppressor lipid sphingosine and enhancing pro-tumorigenic lipid mediator SIP. We propose to further define molecular mechanisms and test the biological significance in mouse models of intestinal cancer. Thus, the specific aims are: 1. To further define the role of sphingosine kinase enzymes in intestinal tumorigenesis. 2. To define the molecular mechanisms involved in the intracellular signaling of sphingosine, 3. We will test the hypothesis that increased intracellular sphingosine and reduced autocrine signaling of 81P brought about by gene deletion of Sphk enzymes is responsible for tumor suppressive action. Dietary sphingomyelin will be used to further Increase sphingosine levels in Sphk knockout mice and we will test whether this dietary manipulation further influences intestinal tumorigenesis in the ApcMin/-t- model. Since sphingolipid levels in the intestine can be altered by dietary means, this research promises to provide a novel means of cancer chemoprevention.

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Sphingolipid mediators regulate cell signaling events and modulate cell proliferation, apoptosis and angiogenesis. We propose that dietary sphingolipid intake, and metabolism in the intestinal tract, produces sphingolipid mediators that suppress intestinal cancer. This research will elucidate mechanisms and attempt to develop a novel way of intestinal cancer prevention.

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Mayo Clinic, Arizona
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