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.