Transposon-based screens for colorectal cancer genes

基于转座子的结直肠癌基因筛选

• 批准号: 7652862
• 负责人: Robert T Cormier
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652862
• 关键词: A Mouse; APC gene; Abbreviations; Accounting; Address; Affect; Atlases; Benign; Biological Assay; Biological Markers; Cancer Etiology; Candidate Disease Gene; Cell Culture Techniques; Cells; Cessation of life; Characteristics; Clinical Management; Colorectal Cancer; Data Set; Development; Disease; Disease Progression; Epithelial Cells; Event; Fright; Future; Gastrointestinal tract structure; Gene Mutation; Gene Transfer Techniques; Generations; Genes; Genetic; Genetic Screening; Genome; Genomics; Goals; Grant; Hand; Human; Individual; Induced Mutation; Insertional Mutagenesis; Intestinal Cancer; Intestinal Neoplasms; Inverted Terminal Repeat; Lead; Learning; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Metastatic Adenocarcinoma; Methods; Mission; Modality; Modeling; Molecular; Murine leukemia virus; Mus; Mutate; Mutation; National Cancer Institute; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Pattern; Phenotype; Polyps; Publishing; Role; Second Primary Neoplasms; Site; Sleeping Beauty; Somatic Mutation; Staging; Study models; System; Testing; Therapeutic; Tissues; Transgenes; Transposase; Tumor Suppressor Genes; United States; Work; adenoma; base; cancer genetics; cancer genome; effective therapy; gene discovery; high risk; insight; mouse model; novel; public health relevance; tumor; tumor progression; tumorigenesis; vector; villin

DESCRIPTION (provided by applicant): The development of colorectal cancer (CRC) is a serious and feared malignancy, and the second leading cause of cancer-related death in the United States. Much is known about how CRC develops at early stages, but much remains to be learned about progression of this disease. Clearly it would be desirable to discover the genes and genetic pathways that lead to CRC progression such as metastases. Biomarkers that could be used to detect CRC and to predict tumor progression (invasion/metastasis) are desperately needed in the clinical management of patients at high risk for CRC - such as patients who've had polyps removed in the past. This project can help to address the mission of the National Cancer Institute's plan to create a comprehensive human cancer genome atlas. While some insight has been gained in the somatic changes that can occur in CRC, it is likely that much remains to be learned. An unbiased screen for somatic mutations that could cause CRC or accelerate malignancy after initiation by specific known human CRC mutations would be invaluable. The identification of CRC cancer genes, and the patterns in which these mutations occur in individual cases, will certainly guide future therapies. It is the main goal of this grant to model CRC using a novel system for random, Sleeping Beauty (SB) transposon-based, somatic insertional mutagenesis developed by Drs. Largaespada. Methods to induce CRC by transposition of SB transposon vectors in have already been established by Dr. Largaespada and Dr. Cormier. Candidate CRC genes will be tested for their ability to cause cancer by mouse transgenesis and other assays. The results will also be compared to human CRC genetic alterations. Relevance: This project seeks to define what genes, when altered in GI tract epithelial cells, cause CRC. It is critical to know what genes cause CRC so that effective therapies for this cancer can be developed. A mouse model of CRC will be created in which all the mutated genes that cause the CRC can be identified. Then a subset of these genes will be analyzed carefully for their individual effects in cell and mouse models. PUBLIC HEALTH RELEVANCE: This proposal describes work done in mice to understand how colorectal cancer develops. We will discover what genes, when damaged, can cause these tumors. This will help us decide how best to treat this very common and often lethal disease.

描述(申请人提供)：结直肠癌(CRC)的发展是一种严重和令人畏惧的恶性肿瘤，是美国与癌症相关的死亡的第二大原因。关于早期结直肠癌的发展已知很多，但关于这种疾病的发展仍有许多有待了解的地方。显然，人们希望发现导致结直肠癌进展的基因和遗传途径，例如转移。可以用来检测结直肠癌和预测肿瘤进展(侵袭/转移)的生物标记物在结直肠癌高危患者的临床管理中是迫切需要的--例如过去曾切除息肉的患者。该项目可以帮助实现国家癌症研究所创建全面人类癌症基因组图谱的计划的使命。虽然已经在结直肠癌的躯体变化中获得了一些洞察力，但很可能仍有很多东西需要了解。在特定已知的人类CRC突变启动后，对可能导致CRC或加速恶性的体细胞突变进行公正的筛查将是非常有价值的。对结直肠癌癌症基因的识别，以及这些突变在个别病例中发生的模式，肯定会指导未来的治疗。这笔赠款的主要目的是使用Largespada博士开发的基于随机、睡美人(SB)转座子的体细胞插入突变的新系统来模拟CRC。Largespada博士和Cormier博士已经建立了通过转座SB转座子载体诱导结直肠癌的方法。候选的CRC基因将通过小鼠转基因和其他测试来测试它们致癌的能力。研究结果还将与人类CRC基因改变进行比较。相关性：该项目试图确定当胃肠道上皮细胞发生改变时，哪些基因会导致结直肠癌。了解导致CRC的基因是至关重要的，这样才能开发出治疗这种癌症的有效方法。将创建一种CRC的小鼠模型，在该模型中可以识别导致CRC的所有突变基因。然后，将仔细分析这些基因的子集，以确定它们在细胞和老鼠模型中的单独作用。与公共卫生相关：这项建议描述了在小鼠身上所做的了解结直肠癌如何发展的工作。我们将发现，当基因受损时，哪些基因会导致这些肿瘤。这将帮助我们决定如何最好地治疗这种非常常见且往往是致命的疾病。