MOLECULAR, CLINICAL APPROACHES COLON CANCER PRECURSORS

结肠癌前体的分子临床方法

• 批准号: 2686767
• 负责人: RAYMOND L WHITE
• 金额: $ 207.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-10 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2686767
• 关键词: colon neoplasms

The adenomatous polyp is an almost essential intermediate in the progression of normal intestinal epithelium to gastrointestinal cancer. Strong support for this view has been provided by clinical and molecular genetic studies of the inherited syndrome, adenomatous polyposis coli (APC), and of sporadic colorectal polyps, thus providing one of the most important windows into the pathogenesis of colon cancer. In pursuing the molecular basis of APC, we identified a tumor suppressor gene, APC, that is now recognized as a primary step in polyp development and progression to cancer. The theme of this Program focuses on the adenomatous polyp: laboratory analysis of its genetic origins, and the molecular and cellular biology of the polyp as a precursor to cancer. Studies of the cellular and molecular changes resulting from mutation of APC form the basis for Project one; our investigations will address functional aspects of the APC protein with regard to its subcellular localization, post-translational regulation and novel binding partners. The second will employ cellular, molecular, biological and genetic approaches to examine the role of cyclooxygenase, a key target of effective chemopreventative agents, in the genesis and progression of adenomatous polyps. Project 3 examines the molecular mechanisms connecting mutations in genes encoding DNA mismatch repair enzymes, which are implicated in a separate form of inherited colon cancer, with observed changes in colon epithelial cells. The fourth seeks to determine the genetic basis for heterogeneity in an attenuated form of the APC syndrome. The fifth project is designed to identify the basis for familial forms of colon cancer that cannot be attributed to mutations in APC or mismatch repair genes. Our preliminary results suggests that several unidentified genes likely account for additional forms of familial colon cancer; in the course of this project, we will identify affected families and carry out initial linkage studies. The Program will support administrative, clinical, tissue procurement and cell culture cores. Use of these core facilities is widespread, as there is extensive interaction among the various projects. In summary, this Program provides an integrated approach to the major precursor to colon cancer, the adenomatous polyp. Our approach is multi-disciplinary with interactive Projects based on molecular and cellular biology, genetics, and clinical characterization. These studies of the adenomatous polyp of the colon offer an unusual and important opportunity for the discovery of new approaches to the prevention of colon cancer through detection and elimination of its precursor, the adenomatous polyp.

腺瘤息肉是几乎必不可少的中间体 正常肠上皮向胃肠癌的进展。 临床和分子提供了对这种观点的强烈支持 遗传综合征，腺瘤性息肉病的遗传研究 （APC）和零星的大息息肉，因此提供了最多的 重要的窗户进入结肠癌的发病机理。追求 APC的分子基础，我们确定了抑制肿瘤基因APC，即 现在被公认为是息肉发展和发展的主要步骤 癌症。该程序的主题着重于腺瘤息肉： 其遗传起源以及分子和细胞的实验室分析 息肉的生物学是癌症的先驱。细胞和 由APC突变引起的分子变化构成了基础 项目一；我们的调查将解决APC的功能方面 蛋白质的亚细胞定位，翻译后的蛋白质 调节和新颖的绑定伙伴。第二个将采用细胞， 分子，生物学和遗传学方法检查的作用 环氧酶是有效化学预防剂的关键靶标 腺瘤息肉的起源和进展。项目3检查 连接编码DNA不匹配基因突变的分子机制 维修酶，与遗传结肠的单独形式有关 癌症，观察到结肠上皮细胞的变化。第四次寻求 确定以衰减形式的异质性的遗传基础 APC综合征。第五个项目旨在确定 家族形式的结肠癌，不能归因于突变 APC或不匹配修复基因。我们的初步结果表明 几个身份不明的基因可能是家族性的其他形式 结肠癌；在这个项目的过程中，我们将确定受影响的 家庭并进行最初的联系研究。该计划将支持 行政，临床，组织采购和细胞培养核心。使用 这些核心设施中的广泛相互作用，因为存在广泛的互动 在各种项目中。总而言之，该程序提供了 结肠癌主要前体的综合方法， 腺瘤息肉。我们的方法是互动的多学科 基于分子和细胞生物学，遗传学和临床的项目 表征。这些关于结肠腺瘤息肉的研究 为发现新的机会提供了一个异常和重要的机会 通过检测和 消除其前体，腺瘤息肉。