Using the Collaborative Cross for Model Studies of Intestinal Cancer

使用协作交叉进行肠癌模型研究

基本信息

批准号：
9308925
负责人：
Linda D Siracusa
金额：
$ 14.91万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9308925
关键词：
APC gene Address Adenocarcinoma Adenomatous Polyposis Coli Affect Age Alcohol consumption Alleles Blood Carcinoid Tumor Catalogs Celiac Disease Chromosome Mapping Colon Colon Carcinoma Colorectal Colorectal Cancer Complex Congenic Strain Coupled Crohn&apos 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 exposure Recombinants Rectal Cancer Rectum Refractory Reproducibility Research Resistance Resolution Resources Risk Risk Factors Running Sex Chromosomes Small Intestinal Adenocarcinoma Small Intestines Stomach Stromal Neoplasm Study models Syndrome Systems Biology Teenagers Tissues Tobacco use Tumor Tissue Variant Woman adenoma attributable mortality autosome 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

项目摘要

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.

使用协作交叉进行肠癌模型研究胃肠道 (GI) 癌症是一种非常普遍且致命的全球性健康问题。能力了解影响正常胃、小肠、结直肠变化的遗传因素癌症发生、生长和进展的组织对于精准医学的目标至关重要。与每种癌症一样，能够在癌症出现之前识别出处于危险中的人可以提供最大的帮助干预和预防危及生命的疾病发展的机会。为了更好地模拟人类疾病，协作交叉（CC）产生并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 是重组自交 (RI) 系，由 8 个近交始祖菌株的基因组贡献，之所以选择，是因为它们与每个近交菌株的进化多样性其他。不同 CC 系内等位基因的独特组合有助于：1) 疾病的识别表型比常见近交实验室菌株中观察到的更为极端，并且2）对影响复杂性状的基因座进行高分辨率绘图的机会。我们的研究提供了一条途径研究、表征和定量单个 CC 系内的胃肠道肿瘤表型。我们建议使用一个致敏背景，即腺瘤性结肠息肉病 (Apc) 基因的突变加上抗性 Mom2R 等位基因，并将这些小鼠与 CC 系进行一步杂交，以筛选显性的导致肿瘤发生增加或肿瘤特征改变的修饰剂。我们已经整合了一个突变Apc 等位基因，因为 APC 基因是胃、小肠和结直肠中突变最多的 5 个基因之一人类癌症。 CC 线的使用加上我们独特的、寿命长但敏感的同源菌株为胃肠道癌症的体内研究带来了创新方法。