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。 该组织在有丝分裂上 非常活跃，每天约有1011个细胞分裂。 令人惊讶的是，大肠癌的发病率只会急剧上升 在生活的第六十年之后，表明稳态必须是 由许多监管层维护。 这个法规是 遭受常染色体显性癌症的人违反 综合征称为家族性腺瘤性息肉病（FAP）。 这个综合征是 以许多可以的结肠腺瘤形成的特征 进展到腺癌。 主要治疗方法是切除或切除 结肠，然后进行辐射和/或化学疗法。 FAP的分子基础开始被理解。 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博士确定了小鼠同源物的突变 腺瘤性息肉病大肠杆菌基因，apcmin。 携带一份副本的小鼠 该突变的整个肠发展了多个腺瘤 道。 拟议的研究的目的是确定这一点的修饰符 表型。 一种方法是基于测试具有的候选基因 与人类结肠癌有关。 如果这些基因的等位基因 影响最小表型，然后影响这些等位基因和最小的组合 是人类疾病的更好模型，应该促进 基因和药物疗法的发展。 其他方法是 旨在通过 映射通过交叉近交菌株或 通过映射在遗传筛查中分离的突变体修饰符。 这样的 修饰符可能会提供有关基因网络的新见解 影响肠道肿瘤。