Transposon-based screens for colorectal cancer genes

基于转座子的结直肠癌基因筛选

• 批准号: 8204554
• 负责人: Robert T Cormier
• 金额: $ 30.39万
• 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/8204554
• 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; Cell model; Cessation of life; Characteristics; Clinical Management; Colorectal; 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; Health; 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; 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（由申请人提供）：结直肠癌（CRC）的发展是一种严重且令人恐惧的恶性肿瘤，并且是美国癌症相关死亡的第二大原因。人们对结直肠癌早期如何发展了解很多，但关于这种疾病的进展仍有很多知识需要了解。显然，人们希望发现导致结直肠癌进展（例如转移）的基因和遗传途径。在CRC高危患者（例如过去曾切除息肉的患者）的临床管理中，迫切需要可用于检测CRC并预测肿瘤进展（侵袭/转移）的生物标志物。该项目可以帮助实现国家癌症研究所计划的使命，即创建全面的人类癌症基因组图谱。虽然人们对结直肠癌可能发生的躯体变化有了一些了解，但可能还有很多东西有待了解。对可能导致结直肠癌或在特定的已知人类结直肠癌突变引发后加速恶性肿瘤的体细胞突变进行公正的筛查将是非常有价值的。结直肠癌癌症基因的鉴定以及这些突变在个体病例中发生的模式肯定会指导未来的治疗。这笔赠款的主要目标是使用由 Drs. 开发的基于睡美人 (SB) 转座子的随机体细胞插入突变的新型系统来模拟 CRC。拉加斯帕达。 Lagaespada 博士和 Cormier 博士已经建立了通过 SB 转座子载体转座来诱导 CRC 的方法。候选 CRC 基因将通过小鼠转基因和其他检测来测试其致癌能力。结果还将与人类结直肠癌基因改变进行比较。相关性：该项目旨在确定哪些基因在胃肠道上皮细胞中发生改变时会导致结直肠癌。了解导致结直肠癌的基因至关重要，这样才能开发出针对这种癌症的有效疗法。将创建 CRC 小鼠模型，其中可以识别导致 CRC 的所有突变基因。然后，将仔细分析这些基因的子集在细胞和小鼠模型中的个体效应。公共健康相关性：该提案描述了在小鼠中所做的工作，以了解结直肠癌是如何发展的。我们将发现哪些基因受损后会导致这些肿瘤。这将帮助我们决定如何最好地治疗这种非常常见且往往致命的疾病。