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: 9762067
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762067
• 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.

 描述（由申请人提供）：作为一名核医学医师和转化神经科学家，我的长期职业目标是在以患者为导向的研究（POR）中建立独立的职业生涯，重点是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平移正电子发射断层扫描脑成像研究。我的神经科学研究生水平培训重点是用于研究哺乳动物中枢神经系统动态重组的临床前动物模型和湿实验室技术。这种基础科学研究的培训将成为我计划作为临床医生科学家进行的转化研究设计的基础。我的医学培训包括医学院、实习 核医学住院医师实习为我提供了健康和疾病的基础知识，并引导我进入核医学临床专业，我获得了该专业的委员会认证。当我在研究生涯中走向独立时，解决我的知识和培训方面的差距以实现我的长期目标至关重要。 2012 年 1 月 1 日，我被任命为宾夕法尼亚大学 (UPenn) 佩雷尔曼医学院放射学助理教授。尽管​​临床和教学职责负担很重，但我仍然能够在宾夕法尼亚大学追求我对转化神经受体研究的兴趣和热情。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。该 K23 奖项的目标是让我能够集中至少 75% 的时间进行研究并完成本拨款提案中描述的培训，这将帮助我发展成为一名独立研究者。我提出的培训目标将使我能够朝着实现这一目标的逻辑轨迹前进。这些包括（1）获得 PET 定量技术的新知识，以及能够探讨成瘾药物遗传学与渴望尼古丁的行为药理学之间关系的神经受体成像研究的设计； (2) 进行一项新颖的研究，检查精神活性化合物（即尼古丁）和受体占据（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望的神经化学机制 (3) 开发工具来传达我的研究成果，在动态的多学科环境中进行合作，并确保我的研究项目的外部资金。随着研究的发展，我将通过拟议的研究、相关课程、导师和指导委员会的指导、参加研讨会和讲习班以及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新的知识和技能，这对于实现我的职业目标、发展独立研究项目以及在 K23 奖结束时获得 RO1 至关重要。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的相互作用 系统目标烟碱乙酰胆碱受体 (nAChR)，并检查其对多巴胺占据多巴胺 D3 受体的影响，多巴胺 D3 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原理包括（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）无论采用何种疗法，尼古丁戒烟都需要改变 nAChR 分布（3）奖赏、渴望和戒断的调节对于实现戒烟非常重要。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控制。由于目前 FDA 批准的戒烟疗法的成功有限，因此我的研究提案可能会通过进一步加深我们对尼古丁成瘾的神经生物学的了解而产生重大的临床影响，从而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)，拥有得天独厚的条件来支持我的培训需求。我将得到 Robert H. Mach 博士的指导。 （放射化学主任，主要导师）和 Caryn Lerman 博士（CIRNA 主任、联合导师）。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。指导将通过重点课程和参加宾夕法尼亚大学的研讨会和讲习班来补充。除了这些智力资源之外，PET 中心、放射科和 CIRNA 还将提供进行我的研究所需的实用资源，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用研究 PET 扫描设施。通过放射科提供的额外财政支持将使我能够有 75% 作为助理教授的受保护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，以及成功竞争 R01 资金和建立独立研究计划的能力。