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 equ...