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.

利用协作交叉进行肠癌模型研究 胃肠道（GI）癌症是世界范围内的健康问题，既高度流行又致命。的能力 了解影响正常胃、小肠、结直肠改变的遗传因素 组织对癌症的发生、生长和发展的影响对于精准医学的目标至关重要。 与每一种癌症一样，能够在癌症出现之前识别出有风险的人， 有机会干预和预防危及生命的疾病的发展。为了更好地模拟人类 疾病，协作交叉（CC）的产生，并已捕获了巨大的基因组变异 存在于一种哺乳动物物种--小鼠中。CC是由以下产生的重组近交（RI）系： 8个近交创始菌株的基因组贡献，选择这些菌株是因为它们之间的进化多样性 其他.不同CC系内等位基因的独特组合促进：1）疾病的鉴定 表型比在普通近交实验室品系中观察到的更极端，和2） 为影响复杂性状的基因座的高分辨率定位提供了机会。我们的研究代表了一种途径， 研究、表征和定量个体CC系中的GI肿瘤表型。我们建议使用 致敏背景，即腺瘤性结肠息肉病（Apc）基因突变， 抗性Mom 2 R等位基因，并将这些小鼠与CC系在一步杂交中交配以筛选显性Mom 2 R等位基因。 导致肿瘤发生增加或肿瘤特征改变的修饰剂。我们已经整合了一种变异的APC 因为APC基因是胃、小肠和结肠直肠中突变最多的5个基因之一， 人类的癌症使用的CC线加上使用我们独特的，寿命长，但敏感 同类菌株为胃肠道癌的体内研究带来了一种创新方法。