DESCRIPTION (provided by applicant): This is an application for the mentored research Career Development K01 award for Venkatesh Hegde (PhD), a Research Assistant Professor at the University of South Carolina. Dr. Hegde plans to reorient his research efforts and develop his career in the area of prevention of Drug Abuse with the major goal to understand the effects of marijuana components on the immune system by precisely elucidating mechanisms. The candidate seeks three years of protected time and support to obtain advanced training in new fields of research, and towards career development activities necessary to become an independent investigator. Cannabis or marijuana is the most widely consumed illicit drug in United States and its abuse is a major public health issue. In addition to behavioral, psychological and emotional adverse effects, cannabinoid compounds present in marijuana can cause significant immune-altering effects. Dr. Hegde's exciting preliminary results point to a new mechanism of immune-dysfunction caused by cannabinoids, involving robust induction of myeloid-derived suppressor cells (MDSC) in vivo via specific receptor-mediated mechanisms. These potent suppressor cells are known to dampen the immune system's capacity to fight tumors and infections. The central hypothesis of the proposed research is that induction of functional MDSC and its associated molecular networks by cannabidiol (CBD) is an important mechanism of immunosuppression with major biological significance. In Aim 1, Dr. Hegde will investigate the role of microRNA-mediated regulatory pathways involved in the induction of functionally active MDSC by CBD from bone marrow precursors. He will specifically study the mechanism of down-regulation and role of miRNA-706 and miRNA-455 in the regulation of their target transcription factors Stat1 and Stat6, and in-turn, Arginase 1 and iNos enzymes critical for the immunosuppressive function of MDSC. In Aim 2, he will investigate its impact on tumor progression and anti-tumor immune response in vivo using CBD-sensitive and CBD-resistant tumor models. With an accomplished mentoring team lead by Dr. Mitzi Nagarkatti, Professor and Chair at the USC School of Medicine, with the new cutting-edge facilities for epigenetics/ miRNA research, Dr. Hegde will carry out these experiments while obtaining intensive training in several advanced methodologies and will undergo overall career development including training in grantsmanship. With this K01 award, the candidate will establish a strong knowledgebase and expertise, generate sufficient pilot data, and develop a competent R01 level grant application to successfully launch his independent research career in this unique line of research.

PUBLIC HEALTH RELEVANCE: Improved understanding of precise immunosuppressive mechanisms in response to cannabinoid constituents is critical for a better awareness of potential immune-related risks associated with marijuana drug abuse.