Effect of dietary omega 3 fatty acids on colitis and colon cancer development in

描述(申请人提供)：炎症是结肠癌发生发展的重要危险因素。建议通过补充omega-3或n-3脂肪酸来调节饮食中的炎症，以降低炎症和癌症风险。出乎意料的是，我们的实验室最近显示，富含n-3脂肪酸二十二碳六烯酸的鱼油(富含DHA=DFO的鱼油)可促进实验诱导的结肠炎和发展为粘液腺癌。这些肿瘤是在人体相当剂量的3、5和8克DFO/d(2000千卡)下观察的。DFO还显著缩短了肿瘤形成的时间。从机理上讲，n-3脂肪酸被认为通过改变脂肪酸进入免疫细胞的脂筏并减少细胞信号来影响炎症。在多种情况下，先天免疫反应降低可能会导致负面结果。这对炎症性肠道疾病非常重要，这些疾病被认为是由于对胃肠道细菌的先天免疫反应受损而引起的。在美国，鱼油补充量继续快速增加。添加到这些补充剂中的n-3脂肪酸的类型差别很大。然而，与疾病结局相关的n-3来源的研究较少。这项研究的长期目标是通过饮食策略降低结直肠癌风险。这项建议的短期目标是确定在我们的结肠癌进展模型中n-3脂肪酸DHA的促进作用是否也与其他n-3脂肪酸(EPA)或其组合一起观察，这在补充剂中是典型的。该提案针对这些目标提出了以下具体目标：在实验性结肠炎小鼠模型中，建立调节炎症和结肠癌进展的n-3脂肪酸的剂量、来源和红细胞含量。我们假设，EPA单独或EPA：DHA的低组合不会促进结肠炎和加速发育不良，与DHA观察到的方式类似。我们将检验这一假设：a)利用SMAD3-/-小鼠结肠炎模型，喂饲不同来源的n-3(DHA和EPA)，诱发结肠炎并测量炎症/异型增生，b)给抗结肠炎的小鼠喂饲不同来源的n-3(DHA和EPA)，诱导结肠炎并测量炎症/异型增生，c)确定RBC中的n-3脂肪酸掺入与结肠炎严重程度相关的n-3脂肪酸。拟议中的项目通过提供数据支持呼吁使用与摄入量、炎症和结肠癌进展相关的红细胞指数来设定n-3脂肪酸摄入量的最大可容忍上限，从而产生了很大的影响。这项研究还将有助于基本理解易感模型如何告知与膳食补充剂相关的风险以及未来人类研究的潜在风险/益处。

DESCRIPTION (provided by applicant): Inflammation is an important risk factor for progression of colon carcinogenesis. Dietary modulation of inflammation via supplementation by omega-3 or n-3 fatty acids is proposed to reduce inflammation and cancer risk. Unexpectedly, our laboratory recently showed that fish oil enriched with the n-3 fatty acid docosahexaenoic acid (fish oil enriched with DHA=DFO) promoted experimentally induced colon inflammation and progression to mucinous adenocarcinoma. These tumors were observed at human equivalent doses of 3, 5 and 8 grams of DFO/d (2000 kcal). DFO also significantly reduced the time to tumor formation. Mechanistically, the n-3 fatty acids are proposed to influence inflammation by altering the incorporation of fatty acids into the lipid raft of immune cells and reducing cell signaling. There are multiple situations where reduced innate immune responses may result in negative outcomes. This is highly significant to inflammatory bowel diseases that are proposed to result from impaired innate immune responses to bacteria in the gastrointestinal tract. Fish oil supplementation continues to rapidly increase in the US. The type of n-3 fatty acid added to these supplements varies widely. However, the source of n-3 associated with disease outcome is less widely studied. The long-term goal of this research is to reduce colorectal cancer risk using dietary strategies. The short-term goal of this proposal is to determine if the promotional effect of the n-3 fatty acid DHA in our model of colon cancer progression is also observed with other n-3 fatty acids (EPA) or a combination, typical in supplements. The proposal addresses these goals with the following specific aim: establish dose, source and red blood cell content of n-3 fatty acids that modulate inflammation and colon cancer progression in a mouse model of experimental colitis. We hypothesize that EPA alone or lower combinations of EPA:DHA will not promote colitis and accelerate dysplastic development in a manner similar to that observed with DHA. We will test this hypothesis a) utilizing the SMAD3-/- mouse model of colitis fed diets varying the source of n-3 (DHA and EPA), induce colitis and measure inflammation/dysplasia, b) SMAD3 colitis resistant litter mates fed diets varying the source of n-3 (DHA and EPA), induce colitis and measure inflammation/dysplasia and c) determine the n-3 fatty acid incorporation into the RBC that correlates with colitis severity. The proposed project has high impact by providing data supporting a call for a maximum tolerable upper limit for n-3 fatty acid intake using a red blood cell index correlated with intake, inflammation and colon cancer progression. This research will also contribute to the basic understanding of how susceptible models can inform the risks associated with dietary supplementation and potential risk/benefit for future human studies.