Mechanisms of Mutant Epidermal Growth Factor Receptor Induced Lung Tumorigenesis

项目摘要。这份提案描述了候选人从被指导者过渡到 独立阶段的独立之路K99/R00奖。在整个K99阶段， 获奖候选人由纪念斯隆-凯特琳癌症中心的哈罗德·瓦默斯医生指导 (MSKCC)。在此期间，她开发了她的独立研究计划，建立在她的科学基础上 在耶鲁大学获得了终身教职助理教授的职位(2010年7月开始) 大学病理学系和耶鲁大学NCI指定的综合体成员 癌症中心。该奖项的Roo独立阶段。耶鲁大学将提供机构 支持，包括充足的资源、职业发展活动和相互作用的机会 科学家和临床医生帮助候选人实现她的目标。 这项研究的重点是肺癌，这是全球最常见的癌症。候选人已生成 两种基于突变型表皮生长因子受体表达的小鼠肺癌模型 (EGFR)在肺上皮细胞中。她已经证实，肺癌相关的EGFR突变体可以 启动肺肿瘤形成，是维持肿瘤所必需的，并已在这些细胞中建立了耐药性模型 老鼠。 本研究拟测定山羊EGFR的表型和临床行为 突变的肺肿瘤受以下因素的影响：1)突变的EGFR的表达水平；2)其他 EGFR家族成员；以及3)协作性基因损伤。具体目标是使用这些新鼠标 模型：1)阐明突变的EGFR诱导肺上皮细胞转化的机制； 2)发现与突变的EGFR在肺肿瘤发生中协同作用的基因。在小鼠模型中的发现将 在人类肺癌标本中得到验证。

Project Summary. This proposal describes plans for the candidate's transition from the mentored to the independent phase of the Pathway to Independence K99/R00 award. Throughout the K99 phase of this award the candidate was mentored by Dr. Harold Varmus at Memorial Sloan-Kettering Cancer Center (MSKCC). During this time she developed her independent research program, built on her scientific knowledge and obtained a tenure-track Assistant Professor position (beginning in July 2010) at Yale University in the Department of Pathology and membership in the Yale NCI-designated Comprehensive Cancer Center. For the ROO independent phase of this award. Yale University will provide institutional support, including ample resources, career development activites and opportunities for interactions between scientists and clinicians to help the candidate achieve her goals. The research focuses on lung cancer, the most common cancer worldwide. The candidate has generated two mouse models of lung cancer based on expression of mutant Epidermal Growth Factor Receptors (EGFRs) in lung epithelial cells. She has established that the lung cancer-associated EGFR mutants can initiate lung tumorigenesis, are required for tumor maintenance and has modeled drug resistance in these mice. The goats of this research proposal are to detemnine how the phenotype and clinical behaviour of EGFR mutant lung tumors are influenced by: 1) the levels of expression of mutant EGFR; 2) the presence of other EGFR family members; and, 3) cooperating genetic lesions. The specific aims are to use these new mouse models to: 1) Elucidate the mechanisms of mutant EGFR-induced transfomnation of lung epithelial cells; and, 2) Identify genes that cooperate with mutant EGFR in lung tumorigenesis. Findings in the mouse models will be verified in human lung cancer specimens.