OXIDATIVE DNA DAMAGE IN ULCERATIVE COLITIS TUMORIGENESIS

这项建议的重点是肿瘤发生的最早阶段： DNA损伤，这是一系列遗传事件的基础， 会导致结肠癌在过去的十年里， 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中的突变和缺失。 抑制基因和癌基因。然而，这一过程的核心是 产生基因改变的原因我们的目标是 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）相关结肠肿瘤模型。UC是 结肠粘膜慢性弥漫性炎症性疾病， 结肠癌的风险增加，并且特别适合研究 氧化应激在肿瘤发生中的作用。UC肿瘤被假设为 与广泛的氧化性DNA损伤和突变有关， 目前缺乏将这两个过程联系起来的直接证据。 存在微卫星不稳定性，这是全基因组突变的标志 在UC患者的非肿瘤性粘膜中，我们假设 遗传损伤可能由氧化应激引起， 表型隐匿，直到一个或多个特定的遗传事件 促进肿瘤进展。使用UC模型，以及广泛的 我们已经开发了人体组织数据库，我们将确定是否 氧化性DNA损伤和突变在UC中起主要作用 肿瘤发生几种新型DNA氧化损伤的应用 我们开发了一种新的氧自由基突变检测方法， 将提供一个独特的机会来解开这个潜在的关键 结肠肿瘤发生方面。这些基本知识将直接 通过确定定量测量是否转化为临床问题， 氧化性DNA损伤和突变可用作中间标记物 结肠肿瘤进展，以提高癌症监测。此外，本发明还 我们将进行一项试验性随机、双盲、安慰剂对照 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氧化性DNA损伤和诱变， 可能完全避免肿瘤的发生。

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.