FIBER, SHORT CHAIN FATTY ACIDS AND COLON CANCER

这项互动研究计划的广泛科学目标是 进化出一种系统的生物化学理解， 纤维、脂肪和蛋白质导致结肠上皮细胞 或多或少易受化学致癌物的影响。的重点 建议是关于短链脂肪酸（SCFA）的， 纤维发酵使用致癌物处理过的细胞和生理盐水 对照动物，我们建议表征SCFA的摄取如何进入 结肠细胞改变了这些细胞的生物化学， 它们的增殖状态被改变。三个重要变化 将研究的生物/生化状态为： (1)细胞内pH的变化; (2)结肠细胞代谢（包括能量状态）的变化;以及 (3)导致信号改变的膜脂变化 转导途径（特别是蛋白激酶C，亚型和 亚细胞定位）。 由于有很好的证据表明SCFA对结肠细胞的影响是 在正常细胞与转化细胞中不同，实验将是 在两种细胞中进行。此外，由于近端结肠和远端结肠 具有不同的细胞动力学和SCFA吸收模式，它们将 作为单独的组织处理。生成的数据将阐明 细胞内pH、结肠细胞代谢和细胞内信号传导 调节上皮细胞凋亡的机制受到以下因素的影响： 不同类型和数量的SCFA表征的每一部分， 复杂的过程应该提供重要的基础生物学信息 的colonocytes。 阐明调控的基本机制 如果要建立饮食，结肠上皮细胞是必不可少的 作为一种合理的结肠癌预防策略。

The broad scientific goal of this interactive research program is to evolve a systematic biochemical understanding of how the consumption of fibers, fats, and proteins results in colonic epithelial cells that are more or less susceptible to chemical carcinogens. The focus of this proposal is on short chain fatty acids (SCFA) which are the products of fiber fermentation. Using cells from both carcinogen-treated and saline control animals, we propose to characterize how uptake of SCFA into colonocytes changes the biochemistry of these cells in such a way that their proliferative status is altered. The three important changes in biological/biochemical states that will be investigated are: (1) changes in intracellular pH; (2) changes in colonocyte metabolism (including energy status); and (3) changes in membrane lipids that result in changes in signal transduction pathways (specifically Protein Kinase C, isoforms and subcellular localization). Since there is good evidence that the effect of SCFA on colonocytes is different in normal cells vs transformed cells, experiments will be conducted in both cell types. Further, since the proximal and distal colon have different cell kinetics and SCFA absorption patterns, they will be treated as separate tissues. The data generated will elucidate how intracellular pH, colonocyte metabolism, and intracellular signaling mechanisms, which regulate epithelial cytokinetics, are influenced by different types and amounts of SCFA characterization of each part of this complex process should provide important information on the basic biology of colonocytes. Elucidation of the fundamental mechanisms regulating colonic epithelial cytokinetics is essential if diet is to be established as a legitimate colon cancer prevention strategy.