The influence of nicotinic hepatic metabolism on neuroreceptor substrates of nicotine addiction -
DESCRIPTION (provided by applicant): As a Nuclear Medicine physician and translational Neuroscientist, my long-term career goal is to establish an independent career in patient-oriented research (POR), focused on understanding the changes in brain function which occur in nicotine dependence, and how they can be shaped to achieve cessation and improve public health. My prior training has enabled me to help design and conduct translational positron emission tomography brain imaging studies in humans. My graduate level training in neuroscience focused on pre- clinical animal models and wet-laboratory techniques used to study the dynamic reorganization of the mammalian central nervous system. This training in basic science research will serve as the foundation for the design of the translational studies I plan on pursuing as a clinician-scientist. My medical training including medical school, internship
and Nuclear Medicine residency provided me with fundamental knowledge of health and disease, and directed me to a clinical specialty in Nuclear Medicine, in which I am board certified. As I move to independence in my research career, it is critical that I address gaps in my knowledge and training to achieve my long-term goals. I was appointed to Assistant Professor of Radiology at the University of Pennsylvania's (UPenn) Perelman School of Medicine on January 1, 2012. Despite a significant burden of clinical and teaching responsibilities, I have been able to pursue my interests and passions in translational neuroreceptor research at UPenn. However, to make a significant contribution to the neurobiology of substance abuse, I require additional training and protected research time. The goal of this K23 award is to enable me to focus at least 75% of my time to conduct the research and complete the training described in this grant proposal that will help me develop as an independent investigator. My proposed training objectives will empower me to progress in a logical trajectory towards this goal. These include (1) acquiring new knowledge in PET quantification techniques, and the design of neuroreceptor imaging studies capable of probing the relationship between addiction pharmacogenetics and the behavioral pharmacology of craving of nicotine; (2) conducting a novel study examining the dynamic interaction between a psychoactive compound (i.e., nicotine) and receptor occupancy (α4β2 receptors and dopamine D3 receptors) in order to further understand the neurochemical mechanisms of drug craving (3) developing the tools to communicate my research findings, collaborate in a dynamic multidisciplinary environment, and secure extramural funding of my research program. I will accomplish these training objectives through the proposed research, relevant coursework, guidance from my mentor and mentorship committee, attendance at seminars and workshops, and applied hands-on research training as the research evolves. This multi-faceted approach will empower me with new knowledge and skills critical to achieving my career goals, growing an independent research program and being awarded an RO1 by the end of the K23 award. My proposed research project allows me to expand on my pilot data, specifically exploring differences in hepatic nicotine metabolism and the interaction of nicotine with its central nervous
system target, the nicotinic acetylcholine receptor (nAChR), as well as examine its effect on the dopamine's occupation of the dopamine D3 receptor-a receptor thought to play an important role in the mammalian central nervous system's reward pathway. The scientific and medical rationale for this study include (1) the rates of hepatic nicotine metabolism affect the ability ofa smoker to quit using nicotine replacement therapy (2) changes in nAChR distribution are required for nicotine cessation no matter the therapy (3) modulation of reward, craving and withdrawal are important in achieving cessation. My preliminary data suggests nAChR availability in brain of smokers is governed by hepatic nicotine metabolism. Because current FDA approved smoking cessation therapies have limited success, my research proposal may have a significant clinical impact by furthering our knowledge of the neurobiology of nicotine addiction that will guide current and future smoking cessation treatments. The environment at the University of Pennsylvania, including the Positron Emission Tomography (PET) Center and the Center for Interdisciplinary Research on Nicotine Addiction (CIRNA), is uniquely equipped to support my training needs. I will be mentored by Robert H. Mach, Ph.D. (Director of Radiochemistry, primary mentor) and Caryn Lerman, Ph.D. (CIRNA Director, co-mentor). My mentorship committee includes scientists in the areas of radiochemistry, neuropharmacology, PET quantification and addiction neuroscience. Mentorship will be complemented by focused coursework and participation in seminars and workshops at UPenn. In addition to these intellectual resources, the PET Center, Department of Radiology and CIRNA will provide the practical resources needed to conduct my research, including use of an extensive infrastructure for participant recruitment, medical screening, data management, and to conduct PET brain imaging studies including a state-of-the-art cyclotron facility and dedicated research PET scanning facilities. Additional financial support provided through the Department of Radiology will enable me to have 75% protected time as an Assistant Professor to conduct the proposed training and research and to develop my career. This comprehensive, interdisciplinary mentored approach will enhance my clinical research skills, and my ability to successfully compete for R01 funding, and establish an independent program of research.
