Sphingosine Kinase as a Target for Cancer Chemoprevention

描述（由申请人提供）： 炎症性肠病（溃疡性结肠炎和克罗恩病）是结肠的慢性炎症性疾病。全世界约有400万人受到影响，结肠癌风险增加。结肠炎的常规治疗可以减少活动性疾病的时间，并有助于维持缓解，但这些治疗通常与副作用有关，并且具有边际效果。鞘脂被越来越多地认为是细胞活化、分化和增殖的关键介质，并且已知其介导在结肠炎诱导的结肠癌发生中至关重要的促炎细胞因子的作用。我们已经表明，鞘脂代谢的特异性抑制剂，即鞘氨醇激酶（SK）抑制动物结肠炎。然而，我们还不知道SK抑制剂是否能阻止与结肠炎相关的结肠癌。在这里，我们建议测试的假设，SK抑制剂预防结肠炎小鼠模型中的结肠癌。这些研究应该提供重要的新数据，以确定SK抑制剂是否提供了一种新的方法，可用于预防结肠癌的发展。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (ulcerative colitis and Crohn's) are chronic inflammatory conditions of the colon. Approximately 4 million people world-wide are affected and are at increased colon cancer risk. Conventional treatment of colitis can reduce periods of active disease and help to maintain remission, but these treatments are often associated with side effects and have marginal results. Sphingolipids are being increasingly recognized as key mediators of cell activation, differentiation and proliferation, and are known to mediate the effects of pro-inflammatory cytokines that are of central importance in colitis-induced colon carcinogenesis. We have shown that specific inhibitors of sphingolipid metabolism, i.e. sphingosine kinase (SK) inhibit colitis in animals. However, we do not know yet whether SK inhibitors stop colon cancer associated with colitis. Here, we propose to test the hypothesis that SK inhibitors prevent colon cancer in mouse models of colitis. These studies should provide important new data that will determine if SK inhibitors provide a new approach that will be useful in preventing the development of colon cancer.