Assessing Dynamic Opioid-Dopamine Interactions Using Simultaneous PET/MRI

描述：这个K99/R00项目将支持候选人的培训和职业发展，使其成为一名转化神经科学家，使用创新的神经成像工具来解决药物滥用障碍的临床相关问题。在医学物理和神经科学成像方面有扎实的背景。她正在寻求与成瘾研究相关的三个领域的进一步培训和指导研究经验：(1)成瘾的神经药理学和神经生物学，(2)高级药理学PET/MRI成像方法，以及(3)临床和转化研究技能。候选人将参加教学课程，参加研讨会和会议，并进行实践教程和实验，以获得所需的所有培训。该候选人热衷于成瘾研究，因为大脑神经化学紊乱和随之而来的大脑功能变化在药物滥用障碍的所有阶段都是关键的。随着同步PET/MRI的发明，该候选人具有开发新型PET/MRI综合成像方法并应用于成瘾研究的独特能力。拟议的研究项目与培训活动同时进行，也将促进她发展成为一名独立的科学家，研究涉及滥用物质障碍的神经生物学机制。阿片类药物是治疗疼痛最有效的镇痛药。阿片类药物处方的数量在过去几年中急剧增加，导致与阿片类药物有关的滥用和成瘾也随之增加。处方药物导致的阿片类药物过量死亡人数现在超过了海洛因和可卡因的总和。寻找没有或减少成瘾倾向的有效镇痛药仍然是迫切需要的。这项研究计划的长期目标是解开控制阿片类药物成瘾的神经化学机制，以便更快、更明智地开发用于疼痛管理的药物。在这项K99/R00提案中，作为实现长期目标的第一步，我们的目标是表征阿片受体激动剂诱发的阿片受体调节，并利用新型PET/MRI方法阐明其在体内的功能后果。我们将开发创新的PET/MRI神经化学模型，建立评估阿片类激动剂药物的新框架。本课题的成功完成将(1)建立阿片受体调控阿片-多巴胺相互作用及其与滥用责任关系的知识基础；(2)启用PET/MRI成像指标来评估新药物的滥用责任；(3)允许使用PET/MRI工具来测试成瘾研究中出现的假设。

DESCRIPTION: This K99/R00 project will support training and career development of the candidate to become a translational neuroscientist using innovative neuroimaging tools to address clinical relevant questions of substances of abuse disorders. The Candidate has solid background in medical physics and neuroscience imaging. She is seeking further training and mentored research experience in three areas related to addiction research: (1) neuropharmacology and neurobiology of addiction, (2) advanced pharmacological PET/MRI imaging methods, and (3) clinical and translational research skills. The candidate will take didactic coursework, attend seminar and conference, and perform hands-on tutorials and experiments to obtain all needed training. The candidate is keen in addiction research because perturbed brain neurochemistry and consequent changes in brain function are pivotal in all stages of substances abuse disorders. With the recent invention of simultaneous PET/MRI, the candidate has the unique ability to develop novel integrative PET/MRI imaging methods and apply in addiction research. The proposed research project running in parallel to training activities will also facilitate her develop into an independent scientist investigating the neurobiological mechanisms involve in substance of abuse disorders. Opioid drugs are the most effective analgesics for pain management. The amount of opioid prescriptions has increased dramatically over the past years resulting in an accompanied rise in opioid-related abuse and addiction. Opioid overdose deaths from prescribed drugs now surpass that of heroin and cocaine combined. The pursuit for effective analgesics with no or reduced addictive liability remains an urgent need. The long-term goal of this research program is to disentangle neurochemical mechanisms that govern opioid addiction liability to enable faster and more informed drug development for pain management. In this K99/R00 proposal, as the first step towards achieving the long-term goal, we aim to characterize opioid-agonist evoked opioid receptor regulation and to elucidate its functional consequences in vivo using novel PET/MRI methods. We will develop innovative PET/MRI neurochemical model and establish a new framework for evaluating opioid agonist drugs. Successful completion of this project will (1) establish a knowledge basis of opioid receptor regulation on opioid-dopamine interactions and its relation to abuse liability; (2) enable a PET/MRI imaging metric for assessing abuse liability f novel medications; and (3) permit the use of PET/MRI tools for testing emerging hypotheses in addiction research.