A Variant of Ileal Bile Acid Binding Protein in Colon Cancer

结肠癌中回肠胆汁酸结合蛋白的变体

• 批准号: 6962201
• 负责人: Jeffrey W Smith
• 金额: $ 16.43万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-12 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962201
• 关键词: adenocarcinoma; antibody; binding proteins; biomarker; cancer prevention; cancer risk; chemoprevention; chickens; cholanate compound; colon neoplasms; gastrointestinal epithelium; gene expression; human tissue; ileum; laboratory mouse; laboratory rabbit; microarray technology; molecular weight; neoplastic growth; protein binding; protein localization; protein structure function; recombinant proteins; ursodeoxycholate

DESCRIPTION (provided by applicant): Adenocarcinoma of the colon is the third-leading malignancy in the U.S. and ranks second only to lung cancer as a cause of cancer-related death. This year 150,000 new cases of colorectal cancer will be diagnosed, and nearly 50,000 deaths will result from the disease in North America (http://seer.cancer.gov/cgi-bin/csr/). There is clearly an unmet need for new strategies to treat colon cancer. The proposed study focuses on a bile acid binding protein that is a potential target for chemoprevention in colon cancer. Bile acids were recognized as risk factors in colon cancer more than 30 years ago, but the role of bile acids in the etiology and progression of the disease remains unclear. This proposal focuses on ileal bile acid binding protein (IBABP), a14-kDa protein that binds to bile acids and is expressed in the cytoplasm of epithelial cells of the ileum. A higher molecular weight form of IBABP, called IBABP-Long (IBABP-L) has been identified. IBABP-L arises from an alternative transcription start site and encodes a form of IBABP with a 49-residue N-terminal extension. Most significantly, mRNA encoding IBABP-L is up-regulated in human colon cancers by 20- to 50-fold. The hypothesis of this study is that IBABP-L is involved in the onset and progression of colorectal cancer, and that this protein could be an important target for anti-tumor therapy. The Aims of the study are to: 1) Express a recombinant form of IBABP-L and determine if it binds to bile acids, including ursodeoxycholic acid (UDCA), a non-natural bile acid with chemopreventative properties, and 2) Raise antibodies that distinguish IBABP-L and IBABP-S and use these to assess the expression of IBABP-L in human colon adenomas and colon tumors.

描述（由申请人提供）：结肠腺癌是美国第三大恶性肿瘤，仅次于肺癌，是癌症相关死亡的第二大原因。今年，在北美将诊断出150，000例新的结肠直肠癌病例，并且将有近50，000人死于该疾病（http：//seer.cancer.gov/cgi-bin/csr/）。显然，对治疗结肠癌的新策略存在未满足的需求。这项研究的重点是胆汁酸结合蛋白，它是结肠癌化学预防的潜在靶点。30多年前，胆汁酸被认为是结肠癌的危险因素，但胆汁酸在疾病病因和进展中的作用仍不清楚。本研究的重点是回肠胆汁酸结合蛋白（IBABP），一种14-kDa的蛋白质，与胆汁酸结合，在回肠上皮细胞的细胞质中表达。已经鉴定了IBABP的更高分子量形式，称为IBABP-Long（IBABP-L）。IBABP-L由另一个转录起始位点产生，并编码一种具有49个残基N-末端延伸的IBABP形式。最重要的是，编码IBABP-L的mRNA在人结肠癌中上调20至50倍。本研究的假设是IBABP-L参与结直肠癌的发生和发展，并且该蛋白可能是抗肿瘤治疗的重要靶点。本研究的目的是：1）表达IBABP-L的重组形式，并确定其是否与胆汁酸结合，包括熊去氧胆酸（UDCA），一种具有化学预防特性的非天然胆汁酸，和2）产生区分IBABP-L和IBABP-S的抗体，并使用这些抗体评估IBABP-L在人结肠腺瘤和结肠肿瘤中的表达。