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

剖析 microRNA-21 在非小细胞肺癌中的作用

• 批准号: 8323289
• 负责人: Mark Edward Hatley
• 金额: $ 16.85万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323289
• 关键词: Accounting; Adenocarcinoma Cell; Advisory Committees; Agar; Apoptosis; Apoptotic; BRAF gene; Cancer Center; Cancer Etiology; Cancer Patient; Cell Cycle Arrest; Cell Line; Cells; Cessation of life; Chairperson; Childhood Rhabdomyosarcoma; Cisplatin; Clinical; Collection; Critiques; Data; Development; Developmental Biology; Diagnosis; Disease; Dissection; Doctor of Philosophy; Doxorubicin; ERBB2 gene; Early Diagnosis; Environment; Epidermal Growth Factor Receptor; Epithelial Cells; Fellowship; Fostering; Genes; Genetic; Goals; Growth; Human; In Vitro; Individual; Internal Medicine; KRAS2 gene; Knockout Mice; Laboratories; Lung; Lung Adenocarcinoma; MEKs; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mentors; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Profiling; Mus; Mutation; Non-Malignant; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nude Mice; Oncogenes; Oncogenic; PIK3CA gene; Pathogenesis; Pathway interactions; Patients; Pediatric Hematology/Oncology; Pediatrics; Pharmacology; Physicians; Postdoctoral Fellow; Reagent; Regulation; Research; Research Personnel; Research Training; Residencies; Resources; Role; Sampling; Scientist; Staging; Structure; Testing; Texas; Therapeutic Intervention; Time; Training; Training Programs; Transgenic Mice; Tumor Suppressor Genes; Universities; Work; Writing; Xenograft procedure; advanced disease; authority; base; cancer therapy; cancer type; career; career development; cell transformation; gain of function; gene discovery; gene function; insight; loss of function; lung tumorigenesis; meetings; member; mouse model; novel; outcome forecast; overexpression; prevent; professor; programs; research study; telomere; tool; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：该提案描述了为从临床研究员过渡到独立研究者而量身定制的研究培训计划。主要研究者拥有博士学位。细胞调节博士，完成了儿科的结构化住院医师培训计划，并刚刚完成了儿科血液学/肿瘤学的临床研究员培训。本文描述的提案将促进对 microRNA-21 (miR-21) 在非小细胞肺癌 (NSCLC) 发病机制中的作用的了解。在这方面，德克萨斯大学西南分校分子生物学系主任、microRNA 和疾病小鼠模型的世界权威 Eric Olson 博士将成为理想的导师。他过去培养了许多博士后研究员，并赞助了以前和现任的医学科学家。为了加强培训，该计划将聘请内科和药理学教授、肺癌分子基础专家 John Minna 博士、发育生物学主席、首席癌症生物学家和小鼠遗传学家 Luis Parada 博士以及儿科主席 George Lister 博士的专业知识。此外，该咨询委员会不仅会定期对数据、假设和拟议的实验提出建设性批评，而且还会就作为独立和富有成效的医师科学家的职业发展提供宝贵的建议。预计咨询委员会的成员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无价的作用。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 途径负调节因子的表达，从而促进肿瘤发生。拟议的实验将基于这一观察结果，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) 明确 miR-21 促进非小细胞肺癌发病机制，3) 探索 miR-21 抑制作为 NSCLC 的治疗方法。德克萨斯大学西南医学中心分子生物学系和 NCI 癌症中心的结合，通过将不同资源的专业知识融入定制项目，为培训医师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，并从中构建学术生涯。