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。全球约有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疾病活动期，有助于保持缓解，但这些治疗往往与副作用有关，效果不大。鞘磷脂被认为是细胞激活、分化和增殖的关键介质，并被认为是在结肠炎诱导的结肠癌发生中起核心作用的促炎细胞因子的作用。我们已经证明了鞘磷脂代谢的特定抑制剂，即鞘氨醇激酶(SK)可以抑制动物的结肠炎。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，我们建议在小鼠结肠炎模型中检验SK抑制剂预防结肠癌的假设。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，将有助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.