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: 7317792
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7317792
• 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的障碍是缺乏特征良好的动物模型，这些模型概括了人类零星结肠癌的病因。尽管我们从各种化学引起的或遗传编程的塑性模型中从癌症中学到了很多东西，但在这些模型中发展的癌症通常与人类结肠癌在潜伏期，肠道位置或分子签名方面显着不同。以机械性和预防为重点的结肠癌研究需要开发动物模型，这些模型允许精确定时，结肠特定的肠生物学修饰。我们提案的目的是解决PA-06-149中列出的特殊兴趣领域：“开发，表征和利用了胃肠道疾病的新型细胞和动物模型，包括相关的癌症。”为了应对这一挑战，我们为拟议的研究开发了两个具体目标。首先，我们将使用启动子，该启动子驱动碳酸酐酶1（CA1）基因的结肠特异性表达来创建具有CRE重物组合酶的结肠上皮细胞特异性表达的转基因小鼠。该模型对于制造结肠特异性基因敲除小鼠非常有用。 CRE转基因表达的表征将通过PCR分析，免疫组织化学以及将我们的转基因小鼠跨到Rosa26R指标小鼠进行评估。其次，我们将用flox的APC等位基因将CA1-CRE转基因小鼠越过小鼠，以创建对这种关键癌基因的结肠特异性缺失的小鼠。 APC灭活突变是远端结肠零星癌发展的早期分子事件。双转基因小鼠中结肠癌的发展将在基础条件下和炎症剂促进后进行评估。结肠特异性的APC无效小鼠将是零星结肠癌的改进模型。更重要的是，它将确认我们新的CA1-CRE模型的效用和灵活性，以使未来的结肠特异性敲除和转基因小鼠。这项工作对公共卫生至关重要，因为它将成为创造更好的动物模型来研究结肠癌机制的基础。此外，用新的转基因小鼠制造的结肠癌模型将有助于测试其治疗和预防癌症的能力。