Multimodal Investigation of the Neuroimmune System in Opioid Use Disorder

阿片类药物使用障碍中神经免疫系统的多模式研究

• 批准号: 10437943
• 负责人: Eric Andrew Woodcock
• 金额: $ 24.9万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437943
• 关键词: Acute; Applications Grants; Area; Behavior; Biological Markers; Brain; Buprenorphine; Cell Death; Cells; Chronic; Clinical; Clinical Research; Development; Disease; Dose; Early treatment; Environment; Epidemic; Exhibits; Foundations; Future; Goals; Heroin; Human; Image; Immune; Impairment; Individual; Inflammatory; Inflammatory Response; Informal Social Control; Injections; Inositol; Investigation; Laboratories; Lead; Link; Magnetic Resonance Spectroscopy; Maintenance Therapy; Measures; Mentors; Mentorship; Methodology; Microglia; Modeling; Molecular; Monitor; Morphine; Nature; Neurobiology; Neuroimmune; Neuroimmune system; Neuroimmunomodulation; Neurosciences; Opiate Addiction; Opioid; Opioid abuser; Outpatients; Pathologic; Pathway interactions; Patients; Pattern; Phase; Play; Positron-Emission Tomography; Process; Proteins; Protocols documentation; Protons; Relapse; Research; Research Personnel; Research Project Grants; Role; Sampling; Scanning; Shapes; Solid; Substance Use Disorder; Survival Analysis; Techniques; Testing; Time; Training; Translating; United States; Universities; Urine; Withdrawal Symptom; addiction; career; career development; chemokine; clinically relevant; cognitive function; craving; cytokine; design; experience; hands on research; healthy volunteer; improved; in vivo; interest; medical schools; morphine administration; morphine tolerance; multimodal neuroimaging; multimodality; neuroimaging; neuroinflammation; nicotine abuse; nonhuman primate; novel; opioid abuse; opioid use disorder; opioid withdrawal; pain sensitivity; pre-clinical; pre-clinical research; preclinical study; prescription opioid; programs; recruit; research study; response; theories; treatment strategy

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.

项目摘要 本指导研究职业发展建议书（K99/R 00）旨在为候选人提供 高级培训，专家指导和实践研究经验，以促进通往 独立的研究生涯。候选人完成了多模式功能和 光谱神经成像和研究尼古丁和阿片类药物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，候选人提出发展以下方面的专业知识： 正电子发射断层扫描（PET）成像，以研究阿片类药物使用障碍的分子基础 （OUD）。为了实现这一目标，候选人将完成一个全面的两年计划， 在三个关键领域的严格培训：1）PET成像方法和分析; 2）临床研究， 阿片类药物依赖者; 3）在研究中负责任的行为。导师团队拥有以下方面的专业知识： PET成像（Richard卡森博士和Kelly Cosgrove博士）和阿片类药物使用障碍（大卫菲林博士）需要 提供示范性的培训体验。该计划将以高效和支持的方式完成 耶鲁大学医学院的培训环境。K99/R 00独立之路 申请将使候选人能够发展成为一个独立的调查员使用多式联运 神经成像技术研究物质使用障碍，特别是OUD。 当前OUD流行的社会后果是巨大的。极其需要 研究新的治疗靶点。最近，人们对神经免疫系统的兴趣越来越大。 已知阿片类药物在外周和大脑中均发挥急性促炎作用。阿片诱导 神经炎症反应可能在OUD的发展和持续中起重要作用。 临床前和临床研究已经将阿片类药物诱导的神经免疫反应与阿片类药物渴求、阿片类药物依赖和阿片类药物依赖联系起来。 寻求行为、吗啡耐受和阿片类戒断症状。在本申请中，我们建议使用 PET成像，以研究阿片类药物对两种单独和非单独的体内神经免疫系统的影响。 权变研究[11 C] PBR 28 18 kDa转运蛋白（TSPO）水平的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[11 C] PBR 28 PET成像来量化急性阿片类药物- 使用新的人类实验室范例在健康志愿者中诱导神经免疫应答。在Aim中 2、将联合收割机PET TSPO成像与肌肌醇的质子磁共振波谱定量相结合 水平，一个假定的神经胶质标志物。总之，这种多模式神经影像学方法将用于评估神经元的功能。 早期治疗OUD患者与匹配良好的对照的体内神经免疫系统。这些研究将阐明 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。阐明 神经免疫系统在OUD中的作用可能会激发新的治疗策略并改善复发率。