OXIDATIVE DNA DAMAGE IN ULCERATIVE COLITIS TUMORIGENESIS

这一建议集中在肿瘤发生的最早步骤：起源 DNA损伤是一系列基因事件的基础，最终 会导致结肠癌。在过去的十年里，许多事情都得到了澄清 关于导致结肠肿瘤发生的特定遗传事件。 这一过程的基础是关键肿瘤的突变和缺失 抑癌基因和癌基因。然而，这一过程的核心是 这首先会产生基因改变。我们的目标是 为了确定氧化应激在这方面的作用，使用人类 溃疡性结肠炎(UC)相关性结肠肿瘤模型。UC是一种 慢性弥漫性结肠粘膜炎症性疾病 增加患结肠癌的风险，这是唯一适合研究 氧化应激在肿瘤发生中的作用。UC肿瘤被假设为 与广泛的DNA氧化损伤和突变有关，但 目前缺乏将这两个过程联系起来的直接证据。 微卫星不稳定性是全基因组突变的一个标志。 在UC患者的非肿瘤性粘膜中，我们假设 基因损伤可能是由氧化应激和残留 在一个或多个特定的遗传事件之前，表型是神秘的 加速肿瘤进展。使用统一通信模式和广泛的 我们已经开发的人体组织数据库，我们将确定是否 DNA氧化损伤和突变在UC发病中的主要作用 肿瘤发生学。几种新型DNA氧化损伤的应用 检测我们开发的一种新的氧自由基致突变试验 将提供一个独特的机会来解开这一潜在的关键 结肠肿瘤发生的方面。这些基本知识将直接 通过确定定量测量是否可以转化为临床问题 氧化DNA损伤和突变可作为中间标志物 改善癌症监测的结肠肿瘤进展。此外， 我们将进行一项随机、双盲、安慰剂对照的试验 在UC患者中使用膳食补充剂的干预试验 风险。通过防止或减少DNA氧化损伤和突变，它 有可能完全避开肿瘤的发生。

This proposal focuses on the earliest steps in tumorigenesis: the origin of DNA damage that underlies the chain of genetic events that ultimately results in colonic cancer. Much has been elucidate in the past decade regarding the specific genetic events that lead to colonic tumorigenesis. Fundamental to this process are mutations and deletions in key tumor suppressor genes and oncogenes. However, central to this is the process that produces the genetic alterations in the first place. Our objective is to establish the role of oxidative stress in this regard, using the human model of ulcerative colitis (UC)-associated colonic neoplasia. UC is a chronic and diffuse inflammatory disease of the colonic mucosa with an increased risk of colon cancer, and is uniquely suited for studying the role of oxidative stress in tumorigenesis. UC neoplasia is hypothesized to be associated with widespread oxidative DNA damage and mutation, but direct evidence linking the two processes in currently lacking. Microsatellite instability, a marker of genome wide mutations, is present in non-neoplastic mucosa of patients with UC and we hypothesize that the genetic damage may be caused by oxidative stress and remains phenotypically occult until one or more specific genetic events precipitate neoplastic progression. Using the UC model, and the extensive human tissue database we have already developed, we will determine whether oxidative DNA damage and mutagenesis play a primary role in UC tumorigenesis. The application of several novel oxidative DNA damage assays a new oxygen free radical mutation assay that we have developed will provide a unique opportunity to unravel this potentially critical aspect of colonic tumorigenesis. This basic knowledge will be directly translated to clinical issues by determining if quantitative measurement of oxidative DNA damage and mutation can be used as intermediate markers of colonic neoplastic progression to improve cancer surveillance. Further, we will perform a pilot randomized, double-blind, placebo controlled intervention trial using dietary supplements in UC patients at highest risk. By preventing or decreasing oxidative DNA damage and mutagenesis, it may be possible to circumvent tumorigenesis entirely.