This proposal described a tailored basic research training program for the transitionfrom post-doctoral fellow to independent investigator. The principle investigator has aPh.D. in Cell Regulation, completed a structured residency training program in Pediatricsand is near the completion of clinical fellowship training in PediatricHematology/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. EricOlson the chairman of Molecular Biology at the University of Texas Southwestern and aworld's authority on mouse models of microRNA and disease will serve as an idealmentor. He has trained numerous post-doctoral fellows in the past and has sponsoredprevious and current physician scientists. To enhance the training, the program willenlist the expertise of Dr. John Minna, Professor of Internal Medicine and Pharmacologyan expert in the molecular basis of lung cancer, Dr. Luis Parada, Chairman ofDevelopmental Biology a premier cancer biologist and mouse geneticist, and Dr. GeorgeLister, Chairman of Pediatrics. Furthermore, this advisory committee will not onlyprovide regular constructive criticism of data, hypotheses, and proposed experiments butinvaluable advice regarding career development as an independent and productivephysician scientist. It is also expected that the members of the advisory committee willbe invaluable in offering their expertise and unique reagents to foster the research plan. The research will focus on elucidating the molecular mechanisms underlying the roleof miR-21 in the progression of non-small cell lung cancer. Recent work in the Olsonlaboratory has established that miR-21 expression modifies the progression of NSCLC ina mouse model of NSCLC. The proposed experiments will build on this observationutilizing transgenic mouse models and tumor cell lines from these models to determinethe importance of miR-21 in lung cancer and the mechanism through which miR-21contributes to non-small cell lung cancer development.
The specific aims i nclude: 1)Determine the role of miR-21 in development NSCLC in vivo, 2) Define the mechanismsresponsible for miR-21 promotion of NSCLC pathogenesis, 3) Explore miR-21 inhibitionas therapy for NSCLC. This will be the first detailed functional analysis of miR-21 in vivousing a mouse model of cancer and gain-of-function and loss-of-function miR-21transgenic mice. The combination of the Molecular Biology Department and the NCI-Cancer Center atUT Southwestern provides an ideal setting for training physician-scientist byincorporating expertise from diverse resources into customized programs. Thisenvironment will provide the ideal interdisciplinary setting not only to conduct theproposed experiments but to develop as an independent clinician scientist from which anacademic career can be constructed.
Lung cancer is the most common form of cancer and the leading cause of cancer-related death worldwide. A newly discovered gene, microRNA-21, correlates with poor survival in lung cancer patients. Through this work we will discover the mechanism through which microRNA-21 acts in lung cancer and explore a novel therapy inhibiting microRNA-21 function in a mouse model of lung cancer.
| Hanna, Jason A; Garcia, Matthew R; Lardennois, Alicia et al. (2018) PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma. Oncogene 37:1991-2007 |
| Drummond, Catherine J; Hanna, Jason A; Garcia, Matthew R et al. (2018) Hedgehog Pathway Drives Fusion-Negative Rhabdomyosarcoma Initiated From Non-myogenic Endothelial Progenitors. Cancer Cell 33:108-124.e5 |
| Hanna, Jason A; Drummond, Catherine J; Garcia, Matthew R et al. (2017) Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma. Cancer Res 77:6109-6118 |
| Lakhia, Ronak; Hajarnis, Sachin; Williams, Darren et al. (2016) MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease. J Am Soc Nephrol 27:2319-30 |
| Hanna, J A; Garcia, M R; Go, J C et al. (2016) PAX7 is a required target for microRNA-206-induced differentiation of fusion-negative rhabdomyosarcoma. Cell Death Dis 7:e2256 |
| Kashi, Venkatesh P; Hatley, Mark E; Galindo, Rene L (2015) Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems. Nat Rev Cancer 15:426-39 |
| Chen, Xiang; Stewart, Elizabeth; Shelat, Anang A et al. (2013) Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24:710-24 |
| Hatley, Mark E; Tang, Wei; Garcia, Matthew R et al. (2012) A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 22:536-46 |
