Integrative Medicine for Pain Management in Sickle Cell Disease

项目概要/摘要 镰状细胞病 (SCD) 的特点是慢性疼痛，伴有潜在的氧化应激、炎症、 缺氧和中枢敏化。阿片类药物是 SCD 疼痛治疗的主要手段，但往往效果不佳 并与显着的副作用相关。使用非药物治疗的潜在好处（例如 针灸、催眠、太极拳、瑜伽）已有报道，但由于缺乏系统应用 令人信服的证据。在 SCD 人源化转基因小鼠模型中，电针 (EA) 在不使用麻醉或约束的情况下进行。我们观察到镇痛效果存在个体差异 通过电针，疼痛减轻的强度与外周/中枢的表达呈正相关 炎症介质。需要探索不同镇痛的潜在机制，以便 制定有效的策略来加强对 EA 反应不佳者的不充分疼痛缓解。具体的 该项目的目标是 1) 确定特定炎症生物标志物（例如物质）的水平是否 P、TNF-α、IL-1β、IL-6) 导致 EA 在镰状小鼠中产生不同的镇痛效果，2) 证明 针对炎症生物标志物的痛觉过敏的潜在机制阻碍了 EA 的镇痛作用 反应不佳者，3) 确定所选循环生物标志物水平与 镰状细胞病患者的针刺镇痛程度及其与静息状态变化的关系 针灸干预下的功能磁共振成像和特定脑神经代谢产物。该组织的首要目标是 指导（K99）奖励的一部分是为候选人提供神经影像疼痛方面的全面培训 她获得终身教授职位并成功领导她所必需的研究和临床技能 自己的独立研究计划。 K99候选人提出的大部分学习和培训 该阶段将在明尼苏达大学在博士的指导下完成。卡尔普纳·古普塔，格雷戈里 Vercellotti 和 Donald Simone 与 Drs 的合作。朱晓红和阿尔·贝茨。外部 密歇根大学 Richard Harris 博士的指导将指导候选人进行 MRI 相关培训 技术。 Lonnie Zeltzer 博士（加州大学洛杉矶分校）是一位领先的综合医学医师科学家，他也将担任 共同导师与共同导师就拟议研究的临床相关方面向候选人提供建议 韦尔切洛蒂博士。这些导师和顾问是分子/生理学领域的世界知名专家 分别与 SCD/癌症或疼痛神经影像学相关的疼痛研究。明尼苏达大学是 由于可用资源（包括致力于该项目的教师），非常适合该项目的 K99 阶段 基础和转化疼痛研究和指导，致力于研究的磁共振成像 (MRI) 扫描仪和最先进的疼痛测试设备，以及各部门充足的实验室和办公空间 医学和放射学。完成该奖项的 K99 部分后，候选人将非常适合 过渡到终身教授职位。

Project Summary/Abstract Sickle cell disease (SCD) is characterized by chronic pain with underlying oxidative stress, inflammation, hypoxia and central sensitization. Opioids are the mainstay of pain therapy for SCD, but are often ineffective and associated with significant side effects. Potential benefits of using nonpharmacological therapy (e.g. acupuncture, hypnosis, Tai chi, Yoga) have been reported, but not been systematically applied due to lack of compelling evidence. In a humanized transgenic mouse model of SCD, electroacupuncture (EA) was administered without using anesthesia or restraints. We observed individual differences in analgesia produced by EA, and the intensity of pain reduction positively correlated with the expression of peripheral/central inflammatory mediators. The underlying mechanisms of varying analgesia need to be explored in order to develop an effective strategy to potentiate the insufficient pain relief of the poor responders to EA. The specific aims of this project are to 1) determine whether the levels of specific inflammatory biomarkers (e.g. substance P, TNF-α, IL-1β, IL-6) contribute to the varied analgesic effect of EA in sickle mice, 2) demonstrate the mechanisms underlying hyperalgesia that target inflammatory biomarkers hamper the analgesic effect of EA in poor responders, and 3) determine the correlations between the levels of selected circulating biomarkers and the degree of acupuncture analgesia in sickle patients, and how they correlate with the changes of resting state fMRI and specific brain neurometabolites with the intervention of acupuncture. The primary goal of the mentored (K99) portion of the award is to give the candidate the comprehensive training in neuroimaging pain research and clinical skills necessary for her to obtain a tenure track faculty position and successfully lead her own independent research program. The majority of studies and training proposed by the candidate for K99 phase will be completed at the University of Minnesota, under the mentorship of Drs. Kalpna Gupta, Gregory Vercellotti, and Donald Simone, with the collaboration of Drs. Xiao-hong Zhu and Al Beitz. The external mentorship of Dr. Richard Harris from University of Michigan will guide the candidate in training related to MRI techniques. Dr. Lonnie Zeltzer (UCLA), a leading physician scientist in integrative medicine, will also serve as a co-mentor in advising the candidate on the clinically relevant aspects of the proposed studies with co-mentor Dr. Vercellotti. These mentors and consultants are world-renowned experts in either molecular/physiological pain research associated with SCD/cancer, or, pain neuroimaging, respectively. The University of Minnesota is ideal for the K99 phase of the project because of the available resources, including faculty who are committed to basic and translational pain research and mentoring, research-devoted magnetic resonance imaging (MRI) scanners and state-of-the-art pain testing equipment, and ample laboratory and office space in Departments of Medicine and Radiology. Upon completing the K99 portion of the award, the candidate will be well suited to make the transition to a tenure-track faculty position.