Dissection of microRNA-21s role in non-small cell lung cancer

项目摘要/摘要 该提案描述了为过渡量身定做的基础研究培训计划 从博士后到独立研究员。首席调查员有一个 细胞调节博士，完成了儿科住院医师培训计划 并即将完成儿科临床团契培训 血液学/肿瘤学。 本文所述的建议将培养对microRNA-21‘S(miR-21)的指挥 在非小细胞肺癌(NSCLC)进展中的作用。在这方面，埃里克博士 奥尔森是德克萨斯大学西南分校分子生物学主席，也是一位 世界上关于microRNA和疾病小鼠模型的权威将是理想的 门托。他过去培养了许多博士后研究员，并赞助了 前任和现任内科科学家。为了加强培训，该计划将 征求内科和药理学教授约翰·明纳博士的专业意见 肺癌分子基础方面的专家路易斯·帕拉达博士， 发育生物学，首屈一指的癌症生物学家和老鼠遗传学家，以及乔治博士 李斯特，儿科主席。此外，这个咨询委员会不仅将 定期对数据、假设和拟议的实验提供建设性的批评，但 关于职业发展的宝贵建议，认为这是一种独立和富有成效的 内科科学家。预计咨询委员会的成员还将 在提供他们的专业知识和独特的试剂以促进研究计划方面发挥不可估量的作用。 这项研究将集中在阐明这一作用的分子机制 MiR-21在非小细胞肺癌进展中的作用奥尔森研究所最近的工作 实验室已经证实miR-21的表达改变了非小细胞肺癌的进展 一种非小细胞肺癌小鼠模型。拟议的实验将建立在这一观察的基础上。 利用转基因小鼠模型和来自这些模型的肿瘤细胞系来确定 MiR-21在肺癌中的重要性及其机制 有助于非小细胞肺癌的发展。具体目标包括：1) 确定miR-21在体内非小细胞肺癌发生中的作用，2)确定其机制 负责促进miR-21在非小细胞肺癌发病机制中的作用，3)探索miR-21的抑制作用 作为非小细胞肺癌的治疗方法。这将是首次在体内详细分析miR-21的功能。 使用小鼠癌症模型和功能获得和功能丧失的miR-21 转基因小鼠。 分子生物系和美国国立卫生研究院癌症中心的联合 德克萨斯大学西南分校为培养内科科学家提供了理想的环境 将来自不同资源的专业知识整合到定制项目中。这 环境将提供理想的跨学科环境，不仅是为了 建议的实验，但要发展为独立的临床科学家，从 学术生涯是可以构建的。

Project Summary/Abstract This proposal described a tailored basic research training program for the transition from post-doctoral fellow to independent investigator. The principle investigator has a Ph.D. in Cell Regulation, completed a structured residency training program in Pediatrics and is near the completion of clinical fellowship training in Pediatric Hematology/Oncology. The proposal described herein will foster a command on microRNA-21's (miR-21) role in the progression of non-small cell lung cancer (NSCLC). In this regard, Dr. Eric Olson the chairman of Molecular Biology at the University of Texas Southwestern and a world's authority on mouse models of microRNA and disease will serve as an ideal mentor. He has trained numerous post-doctoral fellows in the past and has sponsored previous and current physician scientists. To enhance the training, the program will enlist the expertise of Dr. John Minna, Professor of Internal Medicine and Pharmacology an expert in the molecular basis of lung cancer, Dr. Luis Parada, Chairman of Developmental Biology a premier cancer biologist and mouse geneticist, and Dr. George Lister, Chairman of Pediatrics. Furthermore, this advisory committee will not only provide regular constructive criticism of data, hypotheses, and proposed experiments but invaluable advice regarding career development as an independent and productive physician scientist. It is also expected that the members of the advisory committee will be invaluable in offering their expertise and unique reagents to foster the research plan. The research will focus on elucidating the molecular mechanisms underlying the role of miR-21 in the progression of non-small cell lung cancer. Recent work in the Olson laboratory has established that miR-21 expression modifies the progression of NSCLC in a mouse model of NSCLC. The proposed experiments will build on this observation utilizing transgenic mouse models and tumor cell lines from these models to determine the importance of miR-21 in lung cancer and the mechanism through which miR-21 contributes to non-small cell lung cancer development. The specific aims include: 1) Determine the role of miR-21 in development NSCLC in vivo, 2) Define the mechanisms responsible for miR-21 promotion of NSCLC pathogenesis, 3) Explore miR-21 inhibition as therapy for NSCLC. This will be the first detailed functional analysis of miR-21 in vivo using a mouse model of cancer and gain-of-function and loss-of-function miR-21 transgenic mice. The combination of the Molecular Biology Department and the NCI-Cancer Center at UT Southwestern provides an ideal setting for training physician-scientist by incorporating expertise from diverse resources into customized programs. This environment will provide the ideal interdisciplinary setting not only to conduct the proposed experiments but to develop as an independent clinician scientist from which an academic career can be constructed.