MODIFIERS OF INTESTINAL NEOPLASIA IN MICE

小鼠肠肿瘤的修饰因子

• 批准号: 2896499
• 负责人: Richard Brott Halberg
• 金额: $ 4.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2896499
• 关键词: cadherins; cell transformation; colorectal neoplasms; gastrointestinal epithelium; gastrointestinal neoplasms; gene interaction; genetic mapping; genetic markers; genetic regulatory element; genetic screening; laboratory mouse; neoplasm /cancer genetics; phenotype; tumor suppressor genes

The intestinal epithelium is self-renewing. This tissue is mitotically very active with approximately 1011 cell divisions per day. Surprisingly, the incidence rate of colorectal cancer only rises sharply after the sixth decade of life, indicating that homeostasis must be maintained by numerous layers of regulation. This regulation is breached in individuals afflicted with an autosomal dominant cancer syndrome called familial adenomatous polyposis (FAP). This syndrome is characterized by the formation of numerous colonic adenomas that can progress to adenocarcinomas. Primary treatment is resection or removal of the colon, followed by radiation and/or chemotherapy. The molecular basis of FAP is beginning to be understood. It arises from mutations in the adenomatous polyposis coli gene. The laboratory of Dr. W. F. Dove identified a mutation in the mouse homolog of adenomatous polyposis coli gene, ApcMin. Mice carrying a single copy of this mutation develop multiple adenomas throughout the intestinal tract. The goal of the proposed study is to identify modifiers of this phenotype. One approach is based on testing candidate genes that have been implicated in human colorectal cancer. If alleles of these genes affect the Min phenotype, then the combination of these alleles and Min is a better model of the human disease and should facilitate the development of gene and drug therapies. The other approaches are designed to identify novel modifiers of the Min phenotype either by mapping a polymorphic modifier isolated by crossing inbred strains or by mapping mutant modifiers isolated in a genetic screen. Such modifiers may provide new insights into the network of genes that can impact intestinal neoplasia.

肠上皮是自我更新的。 该组织是有丝分裂的 非常活跃，每天大约有 1011 次细胞分裂。 令人惊讶的是，结直肠癌的发病率却急剧上升 在生命的六十岁之后，表明体内平衡必须是 由多层监管维持。 该规定是 患有常染色体显性癌症的个体遭到破坏 称为家族性腺瘤性息肉病 (FAP) 的综合征。 这种综合症是 其特征是形成大量结肠腺瘤， 进展为腺癌。 主要治疗是切除或切除 结肠，然后进行放疗和/或化疗。 人们开始了解 FAP 的分子基础。 它出现了 来自腺瘤性息肉病大肠杆菌基因的突变。实验室 W. F. Dove 博士的小鼠同源物中发现了一个突变 腺瘤性息肉病大肠杆菌基因，ApcMin。 携带单个副本的小鼠 这种突变会在整个肠道内形成多个腺瘤 道。 拟议研究的目标是确定这一点的修饰因素 表型。 一种方法是基于测试具有以下特征的候选基因： 与人类结直肠癌有关。 如果这些基因的等位基因 影响 Min 表型，那么这些等位基因和 Min 的组合 是人类疾病的更好模型，应该有助于 基因和药物疗法的发展。 其他方法是 旨在通过以下方式识别 Min 表型的新修饰剂 绘制通过杂交近交系分离的多态性修饰剂或 通过绘制遗传筛选中分离的突变修饰符。 这样的 修饰因子可能为基因网络提供新的见解 影响肠道肿瘤。