Integrative Medicine for Pain Management in Sickle Cell Disease

项目概要/摘要 镰状细胞病（SCD）的特征是慢性疼痛，伴有潜在的氧化应激、炎症， 缺氧和中枢致敏。阿片类药物是SCD疼痛治疗的主要药物，但通常无效 并伴有明显的副作用。使用非药物治疗的潜在获益（例如， 针灸，催眠，太极，瑜伽）已经报道，但由于缺乏系统的应用， 令人信服的证据在SCD的人源化转基因小鼠模型中， 不使用麻醉剂或约束。我们观察到镇痛产生的个体差异 疼痛减轻的强度与外周/中枢神经系统的表达呈正相关 炎症介质。不同镇痛的潜在机制需要探索，以便 制定有效的策略，以加强对EA反应差的疼痛缓解不足。具体 该项目的目的是：1）确定特定炎症生物标志物（例如， TNF-α、IL-1β、IL-6）参与电针对镰状小鼠的不同镇痛作用; 2）电针对镰状小鼠的镇痛作用与电针对镰状小鼠的镇痛作用有关， 靶向炎症生物标志物的潜在痛觉过敏机制阻碍了EA的镇痛作用， 不良反应者，和3）确定所选循环生物标志物的水平之间的相关性， 镰状病人针刺镇痛的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物。的首要目标 该奖项的指导（K99）部分是给候选人在神经影像疼痛的全面培训 她获得终身教职所需的研究和临床技能，并成功地领导她 独立的研究计划。K99候选人提出的大多数研究和培训 该阶段将在明尼苏达大学完成，由Kalpna Gupta博士、Gregory Vercellotti和Donald Simone，与朱晓红博士和Al Beitz博士合作。外部 来自密歇根大学的Richard Harris博士将指导候选人进行MRI相关培训 技术. Lonnie Zeltzer博士（加州大学洛杉矶分校）是整合医学领域的领先医师科学家，他还将担任 共同指导者就拟议研究的临床相关方面向候选人提供建议 博士维切洛蒂这些导师和顾问都是世界知名的分子/生理学专家， 与SCD/癌症相关的疼痛研究，或疼痛神经影像学。明尼苏达大学是 理想的K99阶段的项目，因为可用的资源，包括教师谁是致力于 基础和转化疼痛研究和指导，研究专用磁共振成像（MRI） 扫描仪和国家的最先进的疼痛测试设备，以及充足的实验室和办公室空间的部门， 医学和放射学。完成K99部分的奖励后，候选人将非常适合 过渡到终身教职

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.