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

 描述(申请人提供)：作为一名核医学内科医生和翻译神经学家，我的长期职业目标是在以患者为导向的研究(POR)中建立一个独立的职业生涯，专注于了解尼古丁依赖引起的大脑功能变化，以及如何塑造这些变化来实现戒烟和改善公共健康。我之前的训练使我能够帮助设计和进行人体正电子发射断层扫描脑成像研究。我在神经科学方面的研究生水平培训侧重于临床前动物模型和用于研究哺乳动物中枢神经系统动态重组的湿实验室技术。这种基础科学研究方面的培训将成为我作为临床医生兼科学家计划从事的转化性研究设计的基础。我的医学培训，包括医学院，实习 核医学实习为我提供了关于健康和疾病的基本知识，并指导我学习了核医学的临床专业，在那里我获得了董事会认证。随着我在我的研究生涯中走向独立，我必须解决我的知识和培训中的差距，以实现我的长期目标。2012年1月1日，我被任命为宾夕法尼亚大学佩雷尔曼医学院放射学助理教授。尽管肩负着沉重的临床和教学责任，我仍然能够在宾夕法尼亚大学从事翻译神经受体研究方面的兴趣和激情。然而，为了对药物滥用的神经生物学做出重大贡献，我需要额外的培训和受保护的研究时间。这项K23奖项的目标是使我能够集中至少75%的时间进行研究，并完成这项拨款提案中所述的培训，这将有助于我发展为一名独立的调查员。我提出的培训目标将使我能够朝着这一目标的逻辑轨道前进。这包括(1)获取正电子发射计算机断层扫描定量技术方面的新知识，并设计能够探索成瘾药物遗传学与尼古丁渴求行为药理学之间关系的神经受体成像研究；(2)开展一项新颖的研究，探讨精神活性化合物(即尼古丁)与受体占有率(α4β2受体和多巴胺D3受体)之间的动态相互作用，以进一步了解药物渴求的神经化学机制；(3)开发工具来交流我的研究结果，在动态的多学科环境中开展合作，并确保我的研究项目获得外部资金。我将通过建议的研究、相关的课程作业、我的导师和指导委员会的指导、参加研讨会和研讨会，以及随着研究的进展进行应用实践研究培训来实现这些培训目标。这种多方面的方法将使我获得对实现我的职业目标至关重要的新知识和技能，发展一个独立的研究项目，并在K23奖项结束时获得RO1。我提议的研究项目使我能够扩展我的试点数据，特别是探索肝脏尼古丁代谢的差异以及尼古丁与其中枢神经系统的相互作用。 这项研究的主要目的是研究系统靶点烟碱型乙酰胆碱受体(NAChR)，并检测其对多巴胺占据多巴胺D3受体的影响，该受体被认为在哺乳动物中枢神经系统的奖赏途径中发挥重要作用。这项研究的科学和医学基础包括：(1)肝脏尼古丁代谢率影响吸烟者使用尼古丁替代疗法戒烟的能力(2)无论尼古丁替代疗法如何，尼古丁戒断都需要改变nAChR的分布(3)奖赏、渴望和戒断的调节在实现戒烟中是重要的。我的初步数据表明，吸烟者大脑中nAChR的可获得性受肝脏尼古丁代谢的控制。由于目前FDA批准的戒烟疗法的成功有限，我的研究提案可能会对我们进一步了解尼古丁成瘾的神经生物学产生重大的临床影响，这将指导当前和未来的戒烟治疗。宾夕法尼亚大学的环境，包括正电子发射断层扫描(PET)中心和尼古丁成瘾跨学科研究中心(CIRNA)，配备独特，能够满足我的培训需求。我将由Robert H.Mach博士(放射化学主任，主要导师)和Caryn Lerman博士(CIRNA主任，联合导师)指导。我的导师委员会包括放射化学、神经药理学、PET定量和成瘾神经科学领域的科学家。导师制将通过重点课程作业和参加宾夕法尼亚大学的研讨会和讲习班来补充。除了这些智力资源外，PET中心、放射科和CIRNA还将提供开展我的研究所需的实用资源，包括使用广泛的基础设施来招募参与者、进行医疗筛查、数据管理，以及进行PET脑成像研究，包括最先进的回旋加速器设施和专门的研究PET扫描设施。通过放射科提供的额外财政支持将使我作为助理教授有75%的保障时间来进行拟议的培训和研究，并发展我的职业生涯。这种全面的、跨学科的指导方法将提高我的临床研究技能，以及我成功竞争R01资金并建立独立研究计划的能力。

 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.