Using the Collaborative Cross for Model Studies of Intestinal Cancer

使用协作交叉进行肠癌模型研究

• 批准号: 9179477
• 负责人: Linda D Siracusa
• 金额: $ 20.36万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9179477
• 关键词: Address; Adenocarcinoma; Adenomatous Polyposis Coli; Adolescence; Affect; Age; Alcohol consumption; Alleles; Blood; Carcinoid Tumor; Cataloging; Catalogs; Celiac Disease; Chromosome Mapping; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Complex; Congenic Strain; Coupled; Crohn' s disease; Cystic Fibrosis; DNA; Development; Diagnosis; Diet; Diffuse; Disease; Endocrine; Epstein-Barr Virus Infections; Exhibits; Family history of; Female; Future; Gastrointestinal Neoplasms; Gastrointestinal Polyp; Gastrointestinal tract structure; Gender; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Goals; Growth; Health; Health Status; Helicobacter pylori; Hereditary Nonpolyposis Colorectal Neoplasms; Human; Hybrids; Immune; Inbreeding; Individual; Inherited; Intestinal Cancer; Intestines; Investigation; Laboratories; Lead; Letters; Li-Fraumeni Syndrome; Life; Location; Lymphoma; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Maps; Measures; Modeling; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Obesity; One-Step dentin bonding system; Organ; Partner in relationship; Pathologist; Patients; Persons; Phenotype; Polyps; Predisposition; Preventive therapy; Probability; Radiation; Recombinants; Rectal Cancer; Rectum; Refractory; Research; Resistance; Resolution; Resources; Risk; Risk Factors; Running; Sex Chromosomes; Small Intestinal Adenocarcinoma; Small Intestines; Stomach; Stromal Neoplasm; Study models; Syndrome; System; Systems Biology; Tissues; Tobacco use; Tumor Tissue; Variant; Woman; adenoma; attributable mortality; autosome; base; cancer risk; design; disease phenotype; genetic variant; genomic variation; human disease; in vivo; indexing; innovation; lifetime risk; male; malignant small intestine tumor; malignant stomach neoplasm; men; mitochondrial genome; mortality; mouse model; mutant; novel; offspring; polyposis; precision medicine; prevent; progenitor; stomach surgery; trait; tumor; tumorigenesis

Using the Collaborative Cross for Model Studies of Intestinal Cancer Gastrointestinal (GI) cancers are worldwide health issues that are both highly prevalent and deadly. The ability to understand the genetic factors influencing the change of normal stomach, small intestine, and colorectal tissues towards the initiation, growth and progression to cancer is essential to the goals of precision medicine. As with every cancer, being able to identify people at risk before the cancer appears provides the greatest opportunity to intervene and prevent the development of life-threatening disease. To better model human disease, the Collaborative Cross (CC) was generated and has captured the tremendous genomic variation present within one mammalian species, the mouse. The CC are recombinant inbred (RI) lines created from the genomic contributions of 8 inbred founder strains, chosen because of their evolutionary diversity with each other. The unique combination of alleles within the different CC lines facilitates: 1) the identification of disease phenotypes more extreme than have been observed in common inbred laboratory strains, and 2) the opportunity for high resolution mapping of loci influencing complex traits. Our studies represent an avenue to investigate, characterize, and quantitate GI tumor phenotypes within individual CC lines. We propose to use a sensitized background, namely a mutation in the adenomatous polyposis coli (Apc) gene coupled with a resistant Mom2R allele, and mate these mice with the CC lines in a one-step cross to screen for dominant modifiers that lead to increased tumorigenesis or altered tumor profiles. We have incorporated a mutant Apc allele because the APC gene is one of the top 5 genes mutated in stomach, small intestine, and colorectal cancers in humans. The use of the CC lines coupled with the use of our unique, long-lived, but sensitized congenic strain brings an innovative approach to the in vivo study of GI cancers.

合作交叉法在肠癌模型研究中的应用 胃肠道(GI)癌症是世界性的健康问题，非常普遍，也是致命的。一种能力 了解影响正常胃、小肠、结直肠改变的遗传因素 组织向癌症的起始、生长和进展对于精确医学的目标是必不可少的。 与每种癌症一样，能够在癌症出现之前识别出有风险的人提供了最大的 有机会干预和预防危及生命的疾病的发展。为了更好地为人类建模 疾病，合作交叉(CC)的产生，并捕捉到了巨大的基因组变异 存在于一种哺乳动物物种中，即老鼠。CC是重组自交系(RI)，由 8个近交系创始菌株的基因组贡献，因为它们各自具有进化多样性 其他的。不同CC系中独特的等位基因组合有助于：1)疾病的识别 比在普通近交系实验室品系中观察到的表型更极端，以及2) 对影响复杂性状的基因座进行高分辨率定位的机会。我们的研究代表了一种途径 调查、鉴定和量化单个CC系中的GI肿瘤表型。我们建议使用 致敏背景，即结肠腺瘤性息肉病(APC)基因的突变 抗性Mom2R等位基因，并将这些小鼠与CC系一步杂交，以筛选显性 导致肿瘤形成增加或改变肿瘤轮廓的修饰物。我们已经整合了一个突变的APC 等位基因，因为APC基因是在胃、小肠和结直肠中突变最多的5个基因之一 人类的癌症。CC线路的使用与我们独特的、经久耐用但敏化的 同源菌株为在体胃肠道肿瘤的研究提供了一种创新的方法。