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

 描述（由申请人提供）：作为一名核医学医生和翻译神经科学家，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中发生的大脑功能变化，以及如何塑造它们以实现戒烟和改善公共健康。我之前的培训使我能够帮助设计和进行人类的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训练集中在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。这种基础科学研究的培训将作为我计划作为临床科学家追求的转化研究设计的基础。我的医学训练包括医学院实习 和核医学实习为我提供了健康和疾病的基本知识，并指导我进入核医学临床专业，我在那里获得了委员会认证。随着我在研究生涯中走向独立，我必须解决我的知识和培训方面的差距，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。尽管临床和教学责任的重大负担，我已经能够追求我的兴趣和激情在宾夕法尼亚大学的翻译神经受体研究。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保护研究时间。这个K23奖的目标是使我能够集中至少75%的时间来进行研究，并完成本资助提案中描述的培训，这将有助于我发展成为一名独立的研究者。我提出的培训目标将使我能够在实现这一目标的合理轨道上取得进展。这些包括（1）获得PET定量技术的新知识，以及能够探测成瘾药物遗传学和尼古丁渴望行为药理学之间关系的神经受体成像研究的设计;（2）进行一项新的研究，检查精神活性化合物（即，尼古丁）和受体占用（α4β2受体和多巴胺D3受体），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合作，并确保我的研究计划的校外资金。我将通过拟议的研究，相关的课程，从我的导师和指导委员会的指导，参加研讨会和讲习班，并应用实践研究培训，随着研究的发展，实现这些培训目标。这种多方面的方法将赋予我新的知识和技能，这对实现我的职业目标至关重要，发展独立的研究计划，并在K23奖结束时获得RO 1。我提出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。 系统的目标，烟碱乙酰胆碱受体（nAChR），以及检查其对多巴胺D3受体的多巴胺的占领的效果-一种被认为在哺乳动物中枢神经系统的奖励途径中发挥重要作用的受体。本研究的科学和医学依据包括：（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）无论何种治疗，尼古丁戒烟都需要nAChR分布的变化;（3）奖赏、渴望和戒断的调节在实现戒烟中很重要。我的初步数据表明，吸烟者大脑中nAChR的可用性受肝脏尼古丁代谢的影响。由于目前FDA批准的戒烟疗法取得的成功有限，我的研究建议可能会通过进一步了解尼古丁成瘾的神经生物学而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），具有独特的装备，以支持我的培训需求。我将由罗伯特·H·马赫博士（放射化学主任，主要导师）和Caryn Lerman博士（CIRNA主任，共同导师）。我的导师委员会包括放射化学，神经药理学，PET量化和成瘾神经科学领域的科学家。指导将通过重点课程和参加在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，PET中心，放射科和CIRNA将提供进行我的研究所需的实际资源，包括使用广泛的基础设施进行参与者招募，医学筛查，数据管理，并进行PET脑成像研究，包括最先进的回旋加速器设施和专用研究PET扫描设施。通过放射学系提供的额外财政支持将使我有75%的保护时间作为助理教授进行拟议的培训和研究，并发展我的职业生涯。这种全面的跨学科指导方法将提高我的临床研究技能，以及我成功竞争R 01资金的能力，并建立一个独立的研究计划。

 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.