The influence of nicotinic hepatic metabolism on neuroreceptor substrates of nicotine addiction

烟碱肝代谢对尼古丁成瘾神经受体底物的影响

• 批准号: 10006803
• 负责人: Jacob Dubroff
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006803
• 关键词: Abstinence; Address; Affect; Affinity; Animal Model; Applications Grants; Area; Award; Basic Science; Binding; Biology; Blood; Bolus Infusion; Brain; Brain imaging; Cessation of life; Cigarette; Clinical; Clinical Research; Complement; Consumption; Cotinine; Cyclotrons; Cytochrome P450; Data; Discipline of Nuclear Medicine; Disease; Doctor of Philosophy; Dopamine; Educational Status; Educational process of instructing; Educational workshop; Effectiveness; Environment; Experimental Designs; Exposure to; Extramural Activities; FDA approved; Failure; Financial Support; Foundations; Funding; Future; Goals; Health; Hepatic; Hour; Human; Image; Individual; Infrastructure; Infusion procedures; Interdisciplinary Study; Internships; Investigation; Kinetics; Knowledge; Laboratories; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolism; Methodology; Methods; Molecular; Molecular Probes; Neuraxis; Neurobiology; Neuropharmacology; Neurosciences; Nicotine; Nicotine Dependence; Nicotinic Receptors; Occupations; Pathway interactions; Patient Recruitments; Pennsylvania; Pharmacogenetics; Pharmacology; Physicians; Play; Positron-Emission Tomography; Psychotropic Drugs; Public Health; Radiochemistry; Radiology Specialty; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Research Training; Residencies; Resources; Rewards; Role; Scientist; Secure; Sensory Receptors; Smoker; Smoking Cessation Intervention; Substance abuse problem; Techniques; Testing; Time; Tracer; Training; Universities; Withdrawal; Work; addiction; base; behavioral pharmacology; career; craving; data management; desensitization; design; dopamine D3 receptor; drug craving; hands on research; imaging study; improved; insight; interest; intravenous administration; liver metabolism; medical schools; medical specialties; multidisciplinary; neurochemistry; nicotine cessation; nicotine craving; nicotine exposure; nicotine replacement; nicotine use; novel; patient oriented research; pre-clinical; predictive marker; professor; programs; public health priorities; public health relevance; radiotracer; receptor; receptor binding; receptor density; screening; skills; smoking addiction; smoking cessation; success; tool; translational study; treatment strategy

 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.



项目成果

Reply: Molecular Imaging of Pulmonary Inflammation: Claiming That Vaping Is More Harmful Than Smoking Is Unsupported.

回复：肺部炎症的分子影像：声称电子烟比吸烟更有害的说法没有证据支持。

• DOI: 10.2967/jnumed.123.265570
• 发表时间: 2023
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Wetherill,ReaganR;Dubroff,Jacob
• 通讯作者: Dubroff,Jacob

Frontiers in Neuroscience Imaging: Whole-Body PET.

• DOI: 10.1016/j.cpet.2020.09.014
• 发表时间: 2020-11
• 期刊: PET clinics
• 影响因子: 2.6
• 作者: A. Thaker;Austin L. Chien;J. Dubroff