Colon-specific Transgenic Mouse for Cancer Research

用于癌症研究的结肠特异性转基因小鼠

• 批准号: 7458975
• 负责人: James C. Fleet
• 金额: $ 15.25万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458975
• 关键词: APC gene; Aberrant crypt foci; Accounting; Address; Alleles; Animal Model; Area; Bioinformatics; Biology; Cancer Model; Chemoprevention; Colon; Colon Carcinoma; Condition; Crohn' s disease; DNA Methylation; Defect; Development; Distal; Environmental Risk Factor; Epithelial Cells; Epithelium; Erythroid; Etiology; Event; Foundations; Future; Gastrointestinal Diseases; Gene Expression; Genes; Genetic Enhancer Element; Genomics; Genus Cola; Goals; Grant; Health; Human; Hyperplasia; Immunohistochemistry; Inflammatory; Intestines; Knock-in Mouse; Knock-out; Knockout Mice; Learning; Life Style; Location; Malignant Neoplasms; Maps; Microarray Analysis; Microsatellite Instability; Mismatch Repair; Modeling; Modification; Molecular; Molecular Profiling; Mus; Mutation; NIH Program Announcements; Oncogenes; Physiology; Pliability; Polymerase Chain Reaction; Prevention; Procedures; Public Health; Receptor Gene; Research; Research Personnel; Risk; Rodent Model; TP53 gene; Testing; Time; Tissues; Transgenes; Transgenic Mice; Transgenic Mouse Facility; Transgenic Organisms; Vitamin D3 Receptor; Work; absorption; anticancer research; carbonate dehydratase; design; improved; innovation; interest; knockout gene; novel; prevent; programs; promoter; recombinase; repair enzyme; research study; success; transgene expression; tumor; vector

DESCRIPTION (provided by applicant): A barrier to understanding the molecular etiology of colon cancer is the lack of well-characterized animal models that recapitulate the etiology of human sporadic colon cancer. While we have learned a great deal from cancers resulting from various chemically induced- or genetically programmed-rodent models, the cancers that develop in these models are often significantly different from human colon cancer in terms of latency, intestinal location, or molecular signature. Mechanistic and prevention focused colon cancer research requires the development of animal models that permit precisely timed, colon-specific modification of intestinal biology. The goal of our proposal is to address an area of special interest listed in PA-06-149: "Development, characterization and utilization of novel cellular and animal models of gastrointestinal diseases, including associated cancers." To meet this challenge we have developed two specific aims for the proposed research. First, we will use the promoter that drives colon-specific expression of the carbonic anhydrase 1 (CA1) gene to create a transgenic mouse with colon-epithelial cell-specific expression of Cre recombinase. This model will be useful for making colon specific gene knockout mice. Characterization of Cre transgene expression will be assessed by PCR analysis, immunohistochemistry, and by crossing our transgenic mice to the ROSA26R indicator mouse. Second, we will cross our CA1-Cre transgenic mice to mice with a floxed APC allele to create mice with colon-specific deletion of this critical oncogene; APC inactivating mutations are an early molecular event in the development of sporadic cancer of the distal colon. The development of colon cancer in the double transgenic mice will be assessed under basal conditions and after promotion with an inflammatory agent. The colon-specific APC null mouse will be an improved model of sporadic colon cancer. More importantly, it will confirm the utility and flexibility of our new CA1-Cre model for making future colon-specific knockout and transgenic mice. This work is critical to public health because it will serve as a foundation for making better animal models to study the mechanism of colon cancer. In addition, colon cancer models made with the new transgenic mouse will be useful for testing agents for their ability to treat and prevent cancer.

描述（由申请人提供）：理解结肠癌分子病因学的一个障碍是缺乏能够概括人类散发性结肠癌病因学的良好表征的动物模型。虽然我们从各种化学诱导或基因编程的啮齿动物模型产生的癌症中学到了很多东西，但在这些模型中形成的癌症在潜伏期、肠道位置或分子特征方面通常与人类结肠癌显着不同。以机制和预防为重点的结肠癌研究需要开发动物模型，以允许对肠道生物学进行精确定时、结肠特异性的修改。我们提案的目标是解决 PA-06-149 中列出的一个特别感兴趣的领域：“胃肠道疾病（包括相关癌症）的新型细胞和动物模型的开发、表征和利用。”为了应对这一挑战，我们为拟议的研究制定了两个具体目标。首先，我们将使用驱动碳酸酐酶 1 (CA1) 基因结肠特异性表达的启动子来创建具有结肠上皮细胞特异性表达 Cre 重组酶的转基因小鼠。该模型将有助于制备结肠特异性基因敲除小鼠。 Cre 转基因表达的特征将通过 PCR 分析、免疫组织化学以及通过将我们的转基因小鼠与 ROSA26R 指示小鼠杂交来评估。其次，我们将 CA1-Cre 转基因小鼠与具有 floxed APC 等位基因的小鼠杂交，以产生结肠特异性删除该关键癌基因的小鼠； APC 失活突变是远端结肠散发性癌症发展的早期分子事件。将在基础条件下和用炎症剂促进后评估双转基因小鼠结肠癌的发展。结肠特异性 APC 缺失小鼠将成为散发性结肠癌的改良模型。更重要的是，它将证实我们新的 CA1-Cre 模型在制备未来结肠特异性敲除和转基因小鼠方面的实用性和灵活性。这项工作对公共卫生至关重要，因为它将成为制作更好的动物模型来研究结肠癌机制的基础。此外，用新型转基因小鼠制作的结肠癌模型将有助于测试药物治疗和预防癌症的能力。

项目成果

Generation of a transgenic mouse for colorectal cancer research with intestinal cre expression limited to the large intestine.

• DOI: 10.1158/1541-7786.mcr-10-0195
• 发表时间: 2010-08
• 期刊: Molecular cancer research : MCR
• 作者: Xue Y;Johnson R;Desmet M;Snyder PW;Fleet JC
• 通讯作者: Fleet JC