This K08 Mentored Clinical Scientist Research Career Development Award proposal describes a 5-year training program for the development of an academic career in neuro-oncology for Dr. Mahua Dey. At present, Dr. Dey is a Tenure Track Assistant Professor of Neurosurgery at Indiana University School of Medicine. During her neurosurgery residency training at University of Chicago she spent two years in one of her co- mentor, Dr. Lesniak's neuro-oncology laboratory studying the role of plasmacytoid dendritic cells in malignant glioma. To achieve full research independence, she has identified three key research objectives: (1) To gain proficiency in advanced immunological research techniques, (2) To gain expertise in various transgenic mouse models and (3) To gain proficiency in advanced molecular biology techniques and two key training objectives: (1) Train in oral and written presentation of research findings, including grant preparation and (2) Develop professional skills necessary for a successful academic career. The proposed K08 project will take place in the Department of Neurosurgery at the Indiana University School of Medicine. This vigorous research environment at the IUSM includes ample access to immunology core facility, histology, DNA core facility, microscopy resources and animal housing, and it nurtures an expanding group of translational neuro-oncology researchers. The primary mentor, Dr. Randy Brutkiewicz, a world renound NIH funded tumor immunologist and co-mentor, Dr. Maciej Lesniak, a productive and very well funded neurosurgeon and neuro-oncology researcher, both have more than 10 years of experience with basic immunology and neuro-oncology research and a very successful and established track record of mentoring junior investigators. The candidate will also benefit from the local mentoring committee that collectively have extensive experience in immunology, neuro-oncology, various transgenic mouse models as well as molecular biology, and a strong track record of independent NIH funding and training young investigators. The research project focuses on defining the mechanisms of immunosuppression that renders targeted immunotherapy ineffective in the setting of malignant glioma. This will be accomplished by studying the role of two immunosuppressive cell population: pDCs and Tregs under the central hypothesis: MHC II restricted antigen presentation by plasmacytoid dendritic cells induce Treg cells proliferation and contribute to glioma immunosuppression. The completion of this proposed project will accomplish two important goals: (1) address the well identified critical shortage of well-trained clinician scientists involved in translational research, and (2) address the critical gap in understanding the role of CNS antigen presentation and failure of immunotherapy. As a result the proposed plan will provide training and preliminary data to support an R01 application and allow the applicant to establish a career as an independent researcher using immunological/molecular discovery to address clinically relevant problems. _
This K08 proposal is designed to train a promising physician scientist to become an independent investigator in the field of neuro-oncology, while simultaneously providing mechanistic insight in the immunosuppressive milieu of glioma microenvironment that leads to failure of targeted immunotherapy. Accomplishing the objectives of this proposal will address the recognized shortage of physician-scientists that are pursuing translational research, and will address a critical gap in our understanding of glioma induced immunosuppression as well as CNS antigen presentation and has the potential to cultivate into effective immunotherapy for patients suffering from one of the deadliest known cancers of the modern time.
