Chemoprevention of colitis-associated colon cancer

描述（由申请人提供）：溃疡性结肠炎是结肠炎相关结肠癌（CAC）发展的单一主要风险因素。CAC的终生风险累积可能高达43%，并且CAC占由于炎症性肠病导致的死亡的六分之一。虽然有令人信服的证据表明富含n-3多不饱和脂肪酸（n-3 PUFA，也称为（3 PUFA））的饮食可以抑制结肠炎症和致癌物诱导的结肠癌，但目前还没有已知的CAC非手术化学预防策略。这些观察结果表明，富含n-3 PUFA的饮食可能是预防炎症进展为结肠癌的有效手段，我们的目标之一是在新开发的CAC动物模型中验证这一假设。我们的工作假设认为，n-3 PUFA的化学预防作用至少部分是由两种脂质受体介导的：蛋白激酶C-β II（PKC（II）和过氧化物酶体增殖物激活受体-γ（PPAR（）。这两个实体已被证明是重要的散发性结肠癌的病因，但其在饮食中的结肠脂质信号转导的作用尚未确定，其在CAC中的作用还没有被调查。我们将利用基因敲除小鼠来确定n-3 PUFA的肿瘤抑制作用是否依赖于PKC 3或PPAR（在结肠上皮中）的表达。这些实验的完成将提供临床前的原则证明，使用膳食脂质的化学预防CAC，并将定义生物学上合理的机制，可能会改变CAC的风险，由必需的膳食脂质。我们的假设的证实将提供基本的临床前原理证明，以支持临床试验，以确定饮食n-3 PUFA是否阻止从结肠炎症进展到CAC，将鉴定PKC β 1和PPAR β 1在CAC中的作用，并可能最终为目前没有结肠切除术替代方案的患者提供化学预防的替代手段。

DESCRIPTION (provided by applicant): Ulcerative colitis is the single major risk factor for the development of colitis-associated colon cancer (CAC). Lifetime risk accruals for CAC may be as high as 43%, and CAC accounts for 1 in 6 deaths due to inflammatory bowel diseases. There is no known non-surgical chemopreventive strategy for CAC, although there is compelling evidence that diets that are rich in n-3 polyunsaturated fatty acids (n-3 PUFA, also known as (3 PUFA) suppress both colonic inflammation and carcinogen-induced colon cancer. These observations suggest that diets that are rich in n-3 PUFA may be effective means to prevent progression from inflammation to colon cancer, and one of our objectives is to test this hypothesis in a newly developed animal model of CAC. Our working hypothesis holds that the chemopreventive effects of n-3 PUFA are mediated, at least in part, by two lipid receptors: protein kinase C-beta II (PKC(ll) and peroxisome proliferator-activated receptor-gamma (PPAR(). Both of these entities have been shown to be important in the etiology of sporadic colon cancer, but their role in dietary lipid signaling in the colon has not been defined, and their role in CAC has not been investigated. We will utilize genetic knockout mice to determine if the tumor-suppressive effects of n-3 PUFA are dependent upon the expression of PKCpll or PPAR( in the colonic epithelium. Completion of these experiments will provide pre-clinical proof-of-principle for the use of dietary lipids in chemoprevention of CAC and will define the biologically plausible mechanisms that may account for alteration of CAC risk by essential dietary lipids. Confirmation of our hypotheses will provide essential pre-clinical proof-of-principle in support of clinical trials to determine if dietary n-3 PUFA prevents progression from colonic inflammation to CAC, will identify the role of PKC(ll and PPAR( in CAC, and may ultimately provide an alternative means of chemoprevention to patients who presently have no alternative to colectomy.