Multimodal Investigation of the Neuroimmune System in Opioid Use Disorder

项目摘要 这份有指导的研究职业发展建议书(K99/R00)旨在为候选人提供 高级培训、专家指导和实践研究经验，可帮助您 独立研究生涯。应聘者完成了多模式函数和 光谱神经成像，并调查了尼古丁和阿片滥用的神经生物学后果。 在临床神经科学培训的坚实基础上，候选人建议在以下方面发展专业知识 正电子发射断层成像研究阿片类药物使用障碍的分子基础 (有声)。为了实现这一目标，候选人将完成一项全面的两年计划，该计划将提供 三个关键领域的严格培训：1)PET成像方法学和分析；2)临床研究 阿片类药物依赖者；3)研究中负责任的行为。指导团队在以下方面拥有专业知识 宠物成像(Richard Carson和Kelly Cosgrove博士)和阿片使用障碍(David Fiellin博士)需要 促进模范培训体验。这项计划将在一个富有成效和支持性的 耶鲁大学医学院的训练环境。这条K99/R00独立之路 应用程序将使应聘者能够发展为使用多模式的独立调查员 研究物质使用障碍的神经成像技术，尤其是OUD。 当前OUD疫情的社会后果是巨大的。有极大的需要 研究新的治疗靶点。最近，人们对神经免疫系统越来越感兴趣。 众所周知，阿片类药物在外周和大脑中都会产生急性促炎作用。阿片类药物诱导 神经炎性反应可能在慢性阻塞性肺疾病的发生和发展中起重要作用。 临床前和临床研究已将阿片类药物诱导的神经免疫反应与阿片类药物渴求、阿片类药物- 寻求行为、吗啡耐受性和阿片类药物戒断症状。在此应用程序中，我们建议使用 PET成像研究阿片类药物对体内神经免疫系统的影响 权变研究。[11C]18 kDa转运蛋白(TSPO)水平的PBR28 PET成像被广泛用于 研究体内神经免疫系统。在目标1中，我们将使用[11C]PBR28 PET成像来定量急性阿片类药物- 使用一种新的人类实验室范例在健康志愿者中诱导神经免疫反应。在AIM 2、将PET TSPO成像与质子磁共振波谱技术相结合，对肌醇进行了定量 水平，一个可能的神经胶质标志物。总而言之，这种多模式神经成像方法将用于评估In 早期治疗患者的体内神经免疫系统与配对良好的对照组。这些研究将澄清 急性阿片类药物给药和慢性阿片类药物滥用的神经免疫后果。澄清： 神经免疫系统在OUD中的作用可能会激发新的治疗策略，提高复发率。

Project Summary This mentored research career development proposal (K99/R00) is designed to provide the candidate advanced training, expert mentorship, and hands-on research experience to facilitate a pathway to an independent research career. The candidate completed graduate training in multimodal functional and spectroscopic neuroimaging and investigated the neurobiological consequences of nicotine and opioid abuse. On this solid foundation of clinical neuroscience training, the candidate proposes to develop expertise in positron emission tomography (PET) imaging to investigate the molecular underpinnings of opioid use disorder (OUD). To achieve this goal, the candidate will complete a comprehensive two-year plan which will provide rigorous training in three key areas: 1) PET imaging methodology and analysis; 2) clinical research among opioid dependent individuals; and 3) responsible conduct in research. The mentorship team has expertise in PET imaging (Drs. Richard Carson and Kelly Cosgrove) and opioid use disorder (Dr. David Fiellin) needed to facilitate an exemplary training experience. This plan will be completed in a highly-productive and supportive training environment at the Yale University School of Medicine. This K99/R00 Pathway to Independence application will enable the candidate to develop into an independent investigator using multimodal neuroimaging techniques to study substance use disorders, especially OUD. The societal consequences of the current OUD epidemic are enormous. There is a tremendous need to investigate novel treatment targets. Recently, there has been increased interest in the neuroimmune system. Opioids are known to exert acute proinflammatory effects in both the periphery and brain. Opioid-induced neuroinflammatory responses may play an important role in the development and perpetuation of OUD. Preclinical and clinical research has linked opioid-induced neuroimmune responses to opioid craving, opioid- seeking behavior, morphine tolerance, and opioid withdrawal symptoms. In this application, we propose to use PET imaging to investigate opioid effects on the in vivo neuroimmune system in two separate and non- contingent studies. [11C]PBR28 PET imaging of 18kDa translocator protein (TSPO) levels is widely-used to study the in vivo neuroimmune system. In Aim 1, we will use [11C]PBR28 PET imaging to quantify acute opioid- induced neuroimmune responses among healthy volunteers using a novel human laboratory paradigm. In Aim 2, we combine PET TSPO imaging with proton magnetic resonance spectroscopy quantification of myo-Inositol levels, a putative glial marker. Together, this multimodal neuroimaging approach will be used to evaluate the in vivo neuroimmune system of early-treatment OUD patients vs. well-matched controls. These studies will clarify the neuroimmune consequences of acute opioid administration and chronic opioid abuse. Elucidation of the role of the neuroimmune system in OUD may motivate novel treatment strategies and improve relapse rates.