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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.

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。