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

描述（由申请人提供）：该提案描述了从临床研究员向独立研究者过渡的定制研究培训计划。主要研究者拥有博士学位。在细胞调节，完成了结构化的住院医师培训计划，在儿科，并刚刚完成了临床奖学金培训儿科血液学/肿瘤学。本文所述的提议将促进对microRNA-21（miR-21）在非小细胞肺癌（NSCLC）发病机制中的作用的控制。在这方面，得克萨斯大学西南分校分子生物学主席、microRNA和疾病小鼠模型的世界权威埃里克·奥尔森博士将作为一个理想的导师。他在过去培养了许多博士后研究员，并赞助了以前和现在的医生科学家。为了加强培训，该计划将招募内科和药理学教授John Minna博士，肺癌分子基础专家，发育生物学主席Luis Parada博士，首屈一指的癌症生物学家和小鼠遗传学家，以及儿科主席乔治利斯特博士的专业知识。此外，该咨询委员会将不仅提供定期的数据，假设和拟议的实验建设性的批评，但作为一个独立的和富有成效的医生科学家的职业发展的宝贵意见。咨询委员会的成员也将提供宝贵的专业知识和独特的试剂，以促进研究计划。该研究将重点阐明miR-21在非小细胞肺癌中作用的分子机制。Olson实验室最近的工作已经确定miR-21积极参与NSCLC小鼠模型的发病机制。miR-21降低促凋亡基因和Ras途径的负调节因子的表达，从而促进肿瘤发生。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支持的人支气管上皮细胞和肺腺癌细胞系，以确定miR-21在肺癌中的重要性以及miR-21促进非小细胞肺癌发展的机制。具体目标包括：1）确定miR-21在永生化人支气管上皮细胞中的致癌潜力，2）确定miR-21促进非小细胞肺癌发病的机制，3）探索miR-21抑制作为NSCLC的治疗。分子生物学系和UT西南部的NCI癌症中心的结合，通过将来自不同资源的专业知识融入定制课程，为培训医生科学家提供了理想的环境。这种环境将提供理想的跨学科环境，不仅可以进行拟议的实验，而且可以发展为独立的临床科学家，从而可以构建学术生涯。

DESCRIPTION (provided by applicant): This proposal described a tailored research training program for the transition from clinical fellow to independent investigator. The principle investigator has a Ph.D. in Cell Regulation, completed a structured residency training program in Pediatrics and has just completed 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 pathogenesis 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 non-small cell lung cancer. Recent work in the Olson laboratory has established that miR-21 actively participates in the pathogenesis of in a mouse model of NSCLC. MiR-21 decreases the expression of both pro-apoptotic genes and negative regulators of the Ras pathway thus facilitating tumorigenesis. The proposed experiments will build on this observation utilizing human bronchial epithelial cells and lung adenocarcinoma cell lines supported by transgenic mouse 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 oncogenic potential of miR-21 in immortalized human bronchial epithelial cells, 2) Define the mechanisms through which miR-21 promotes non-small cell lung cancer pathogenesis, 3) Explore miR-21 inhibition as therapy for NSCLC. 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.