The role of transcription factors in the APC pathway

转录因子在APC通路中的作用

• 批准号: 6922889
• 负责人: DUYEN DANG
• 金额: $ 13.15万
• 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/6922889
• 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) 这项提议是为了给Duyen Dang博士颁发K08奖。邓博士毕业于 哈佛大学医学院于1994年毕业。此后，她在内科接受了临床培训 医学和胃肠病学。在过去的两年里，她致力于 约翰斯·霍普金斯大学文森特·杨博士实验室的科学培训 大学医学院。她的研究重点一直是 肠道富集型Kruppel样因子(GKLF)--一种有效的上皮细胞抑制因子 细胞生长，在肠道肿瘤的发生中。 哺乳动物的肠道上皮是一个动态系统，在这个系统中，细胞的增殖是 再加上差异化。这一过程中的异常导致疾病状态。 比如结肠癌。肿瘤抑制基因腺瘤性突变 结肠息肉病(APC)已被证明在 大多数结直肠癌。此应用程序建议建立两个 转录因子CDX2和GKLF作为APC下游调节因子 路径。这些假设是：(1)APC调节CDX2的表达，(2)CDX2 调节GKLF的表达、肠细胞分化和细胞生长；而 CDX2的显性负突变抑制了这一调控，以及(3) 过表达GKLF可降低肿瘤的恶性程度。三个具体目标是 建议检验这些假设：具体目标1：评估APC是否 在转录或转录后水平调节CDX2的表达； 特定目标2：评估突变体CDX2对细胞的显性负效应 GKLF启动子、肠细胞分化和生长抑制；以及特异性 目的：评价GKLF对结肠癌病理生理的影响。 检测GKLF突变并评价GKLF过表达的效果 关于恶作剧。 拟议的研究将有助于理解这些机制。 肠道发育与结直肠肿瘤发生的关系。此外, 杨博士的持续指导与教学方法 这项提议所固有的课程将为邓博士提供一个框架，以 学习课间休息的方法、理论和概念，走上独立的道路 研究生涯。