CREATION AND CHARACTERIZATION OF MOUSE MODELS OF HUMAN L

人类 L 小鼠模型的创建和表征

• 批准号: 6661273
• 负责人: TYLER E. JACKS
• 金额: $ 124.04万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661273
• 关键词: animal genetic material tag; bioengineering /biomedical engineering; chemical carcinogenesis; chemical genetics; cooperative study; disease /disorder model; early diagnosis; gene mutation; gene targeting; genetic models; genetic strain; genetically modified animals; histopathology; laboratory mouse; magnetic resonance imaging; model design /development; neoplasm /cancer diagnosis; neoplasm /cancer genetics; nonsmall cell lung cancer; oncogenes; p53 gene /protein; smoking; technology /technique development; tobacco abuse; tumor suppressor genes

Lung cancer is the third most common cancer in the United States and is the leading cause of cancer related mortality for both men and women, with 171,500 new cases and 165,600 deaths projected for 1998 in this country. Although smoking cessation trends among adults may result in fewer lung cancer cases in the short to intermediate term, smoking rates among young adults seem to be on the rise. In addition, smoking rates in other parts of the world guarantee that lung cancer will remain a major public health problem worldwide for years to come. One reason for the poor rate of survival of individuals diagnosed with lung cancer is the frequently advanced stage of the disease upon presentation. Thus, there is a clear need to characterize markers associated with early-stage lung cancer to improve methods of diagnosis. Novel therapies for the treatment and prevention of the disease are also wanting. The mouse has been used to model human lung cancer extensively over the past several years in a variety of circumstances, including in spontaneous tumor models, chemically-induced models using a variety of agents, and in certain transgenic strains. Although these studies have confirmed that the mouse can be an adequate model of the early stages of human non-small cell lung cancer (NSCLC) (the predominant form of human lung cancer), the methods used in the derivation of these models (e.g., treatment with chemical carcinogens or transgenic expression of viral oncoproteins) and their limited stage of progression has lessened enthusiasm somewhat. This MMHCC team proposes to create novel mouse models of human NSCLC and to characterize these strains in a variety of ways directed toward their proper validation. The strains will harbor targeted activating mutations in the K-ras oncogene (frequently mutated in human NSCLC) and constitutive or conditional loss-of-function mutations in the lung tumor suppressor genes p53 and the Ink4A locus. Existing and future mouse models of NSCLC will be examined by histological analysis in consultation with a veterinary and human clinical pathologist. Mouse tumors will be subjected to extensive DNA and RNA analysis, in part with reference to known molecular changes in human NSCLC and in part in an effort to identify changes that can then be screened for in human tumor samples. The mouse models of NSCLC will be used in cigarette smoke exposure studies and will be used to evaluate investigative chemotherapeutic and chemopreventative agents. A genetic modifier screen will be performed as part of the characterization of one of these strains. Finally, these mouse lung cancer models will be used in the development of novel non-invasive imaging protocols for primary lung tumors and metastatic lesions.

肺癌是美国第三大常见的癌症，是男性和女性癌症相关死亡率的主要原因，1998年预计在该国有171,500例新病例和165,600例死亡。 尽管成年人的戒烟趋势可能会导致短期到中期的肺癌病例较少，但年轻人的吸烟率似乎正在上升。 此外，世界其他地区的吸烟率保证肺癌将在未来几年中在全球范围内仍然是一个主要的公共卫生问题。诊断为肺癌的个体生存率差的原因之一是疾病经常出现的阶段。 因此，显然需要表征与早期肺癌相关的标记以改善诊断方法。 疾病治疗和预防的新型疗法也需要。 在过去的几年中，在多种情况下，该小鼠已被用来广泛建模人类肺癌，包括在自发的肿瘤模型中，使用各种剂和某些转基因菌株在化学诱导的模型中进行化学诱导的模型。 尽管这些研究已经证实，小鼠可以是人类非小细胞肺癌（NSCLC）早期（人类肺癌的主要形式）的早期阶段的适当模型，但用于推导这些模型的方法（例如，使用化学癌症治疗化学癌症或病毒性肿瘤蛋白的转基因表达）以及其有限型阶段的进展较少。 这个MMHCC团队提议创建人类NSCLC的新型鼠标模型，并以各种针对其适当验证的方式来表征这些菌株。 这些菌株将具有K-RAS癌基因（经常在人NSCLC中突变）和肺部抑制基因p53和Ink4a基因座的构成或条件功能丧失突变的靶向激活突变。 NSCLC的现有和未来的小鼠模型将通过与兽医和人类临床病理学家协商进行组织学分析检查。小鼠肿瘤将经过广泛的DNA和RNA分析，部分参考人NSCLC中的已知分子变化，部分是为了确定可以在人类肿瘤样品中筛选的变化。 NSCLC的小鼠模型将用于香烟烟雾暴露研究中，并将用于评估研究性化疗和化学预防剂。 遗传修饰符筛选将作为这些菌株之一的表征的一部分进行。 最后，这些小鼠肺癌模型将用于开发用于原发性肺肿瘤和转移性病变的新型非侵入性成像方案。