Peripheral and central immune contributions to pain chronification

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Project Summary Complex regional pain syndrome (CRPS) is a severely disabling form of chronic pain that can occur after mild trauma such as fracture or minor surgery. There are approximately 50,000 new cases in the US each year that contribute to the estimated $635 billion per year in medical treatment and lost productivity from chronic pain conditions. CRPS shows two distinct phases: an acute phase that demonstrates a prominence of peripheral findings including limb warmth, edema and skin cytokine production, and a chronic phase that exhibits a cool, often atrophic limb with new onset cognitive and emotional deficits. Currently available treatments are limited in efficacy but particularly ineffective during the chronic phase. Monocyte lineage cells are a key component of the innate immune response to injury both peripherally as “inflammatory” monocytes, and centrally, as yolk sac-derived microglia. These cells express similar receptors, making them historically difficult to distinguish, however, discerning their individual, unique contributions is crucial to understanding pain chronification as both cell subsets have been implicated in CRPS. The aim of this work is to use specific genetic and pharmacologic approaches in our well-validated rodent model of CRPS to investigate the contribution of these cells peripherally and centrally to the acute phase and subsequent transition to the chronic phase of CRPS. This will be done using a combination of approaches including the use of two innovative techniques with the potential for translation to humans. Specifically, we will use high- parameter mass cytometry to provide unprecedented systems-wide perspective of the functional status and interactions among all major immune cell subsets. We will also be taking advantage of innovative approaches to monitor glial cell activation over the course of disease progression using the positron emission tomography ligand, 18F-GE-180, targeting the 18 kDa translocator protein, TSPO, to monitor microglial activation in the spinal cord. Successful completion of this work will not only improve our ability to tailor treatments to individual patients and rationally develop new immune-glial directed therapies but will also provide insight into the utility of peripheral immune phenotyping and glial neuroimaging as translatable diagnostic approaches. Dr. Tawfik has a background in anesthesiology, pain medicine and basic pain research with a focus on neuroimmunity. The detailed career development and research plan presented in this application will provide the required resources and mentorship for her to become an expert in three domains critical to her long-term career goals: 1) Clinically-relevant rodent models of pain; 2) Advanced training in the neuroimaging of pain in live subjects; and 3) Application of advanced molecular genetics tools to study individual immune cells.