The role of transcription factors in the APC pathway

转录因子在APC通路中的作用

• 批准号: 6611441
• 负责人: DUYEN DANG
• 金额: $ 13.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611441
• 关键词: adenomatous polyps; athymic mouse; cell differentiation; clinical research; colon neoplasms; gastrointestinal epithelium; gene expression; gene mutation; human tissue; molecular pathology; preneoplastic state; protein structure function; transcription factor

DESCRIPTION (provided by applicant) This proposal is for a K08 Award for Dr. Duyen Dang. Dr. Dang graduated from Harvard Medical school in 1994. Thereafter, she trained clinically in Internal Medicine and Gastroenterology. She has dedicated the past two years to scientific training in Dr. Vincent Yang's laboratory at Johns Hopkins University School of Medicine. The focus of her studies has been the role of the gut-enriched Kruppel-like factor (GKLF), a potent inhibitor of epithelial cell growth, in intestinal tumorigenesis. The mammalian gut epithelium is a dynamic system in which cell proliferation is coupled to differentiation. Aberrations in this process lead to disease states such as colon cancer. Mutations of the tumor suppressor gene Adenomatous Polyposis Coli (APC) have been shown to initiate neoplastic transformation in most colorectal cancers. This application proposes to establish two transcription factors, CDX2 and GKLF as downstream mediators of the APC pathway. The hypotheses are: (1) APC regulates CDX2 expression, (2) CDX2 regulates GKLF expression, enterocyte differentiation, and cell growth; while dominant negative mutations of CDX2 inhibit this regulation, and (3) over-expression of GKLF leads to reduced malignancy. Three specific aims are proposed to test these hypotheses: Specific Aim 1: To evaluate whether APC regulates CDX2 expression at the transcriptional or post-transcriptional level; Specific Aim 2: To evaluate a mutant CDX2 for dominant negative effects on the GKLF promoter, enterocyte differentiation, and growth suppression; and Specific Aim 3: To evaluate the impact of GKLF on the pathophysiology of colon cancer by assessing for GKLF mutations and evaluating the effect of GKLF over-expression on malignancy. The proposed research will contribute to the understanding of the mechanisms underlying intestinal development and colorectal tumorigenesis. In addition, the continued mentorship of Dr. Yang and the didactic and methodology curriculum intrinsic to this proposal will provide Dr. Dang with a framework to learn the methods, theories, and concepts recess to embark on an independent research career.

描述（由申请人提供） 这份提案是为Duyen Dang博士颁发的K 08奖。邓博士毕业于 1994年在哈佛医学院此后，她在内部临床培训 医学和胃肠病学。过去两年，她致力于 在约翰霍普金斯大学杨博士的实验室接受科学培训 大学医学院。她的研究重点是 肠道富集的Kruppel样因子（GKLF），一种有效的上皮细胞增殖抑制剂， 细胞生长，在肠道肿瘤发生中。 哺乳动物肠道上皮是一个动态系统，其中细胞增殖是 再加上差异化。这个过程中的异常导致疾病状态 例如结肠癌。肿瘤抑制基因Adenomatous的突变 大肠息肉病（APC）已被证明可以启动肿瘤转化， 大多数结肠直肠癌。本申请建议设立两个 转录因子，CDX 2和GKLF作为APC的下游介质 通路假设：（1）APC调节CDX 2表达，（2）CDX 2 调节GKLF表达、肠上皮细胞分化和细胞生长; CDX 2的显性负突变抑制这种调节，和（3） GKLF的过表达导致恶性程度降低。三个具体目标是 具体目标1：评估APC是否 在转录或转录后水平调节CDX 2表达; 具体目标2：评价突变体CDX 2对细胞周期的显性负效应。 GKLF启动子、肠上皮细胞分化和生长抑制;和特异性 目的3：通过观察GKLF对结肠癌病理生理学的影响， 评估GKLF突变并评估GKLF过表达的影响 关于恶性肿瘤 这项研究将有助于了解这些机制 潜在的肠道发育和结直肠肿瘤发生。此外，本发明还提供了一种方法， 杨博士的持续指导和教学方法 本提案所包含的课程将为Dang博士提供一个框架， 学习的方法，理论，和概念休会走上独立 研究生涯。