Mechanisms of Mutant Epidermal Growth Factor Receptor Induced Lung Tumorigenesis

表皮生长因子受体突变诱导肺肿瘤发生的机制

• 批准号: 8325970
• 负责人: KATERINA Abigail POLITI
• 金额: $ 24.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325970
• 关键词: Accounting; Address; Affect; Animals; Attention; Award; Behavior; Cancer Model; Cancer Patient; Candidate Disease Gene; Cells; Collaborations; Collection; Comprehensive Cancer Center; Data; Data Set; Development; Disease; Disease Resistance; Doxycycline; Drug resistance; Embryo; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial Cells; Epithelium; Exons; Family; Family member; Gefitinib; Gene Dosage; Gene Expression; Gene Expression Alteration; Genes; Genetic; Genomics; Goals; Goat; Grant; Heterozygote; Homozygote; Human; Incidence; Knockout Mice; Knowledge; Lead; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Modeling; Molecular Profiling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphatidylinositols; Positioning Attribute; Process; Protocols documentation; Publishing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Relapse; Research; Research Proposals; Resistance; Resources; Role; Sampling; Scientist; Specimen; Testing; Tetracyclines; Time; Transgenic Mice; Transgenic Organisms; Tumor Cell Line; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Universities; Validation; Withdrawal; Work; base; cancer genomics; career development; clinical phenotype; cohort; genetic analysis; in vivo; lung carcinogenesis; lung tumorigenesis; meetings; member; mouse model; mutant; novel; overexpression; professor; programs; research study; resistance mechanism; response; sarcoma; success; transgene expression; tumor; tumorigenesis

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.

项目摘要。本建议书描述了候选人从接受指导者过渡到 独立之路K99/R 00奖的独立阶段。在K99阶段， 该候选人在纪念斯隆-凯特琳癌症中心的哈罗德·瓦穆斯博士指导下获得了该奖项 （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， 知识，并获得了耶鲁大学终身助理教授职位（2010年7月开始） 大学病理学系和耶鲁大学NCI指定的综合 癌症中心对于这个奖项的ROO独立阶段。耶鲁大学将提供 支持，包括充足的资源，职业发展活动和互动的机会， 科学家和临床医生来帮助候选人实现她的目标。 该研究的重点是肺癌，这是世界上最常见的癌症。候选人已经产生了 基于突变型表皮生长因子受体表达的两种小鼠肺癌模型 在肺上皮细胞中的EGFR。她已经证实，肺癌相关的EGFR突变体可以 启动肺肿瘤发生，是肿瘤维持所必需的，并在这些肿瘤中具有模型化的耐药性。 小鼠 本研究计划的目的是确定EGFR的表型和临床行为如何影响EGFR的表达。 突变型肺肿瘤受以下因素影响：1）突变型EGFR的表达水平; 2）其他EGFR基因的存在。 EGFR家族成员;和，3）协同遗传病变。具体目标是使用这些新鼠标 1）阐明突变EGFR诱导的肺上皮细胞增殖的机制;和， 2)鉴定在肺肿瘤发生中与突变型EGFR合作的基因。在小鼠模型中的发现将 在人类肺癌标本中得到验证。