Peripheral and central immune contributions to pain chronification

项目概要 复杂区域疼痛综合征 (CRPS) 是一种严重致残的慢性疼痛，可能在轻度疼痛后发生。 外伤，如骨折或小手术。美国每年大约有 50,000 例新病例 每年造成约 6,350 亿美元的医疗费用和慢性疼痛造成的生产力损失 条件。 CRPS 显示两个不同的阶段：急性期，表现出外周血管的突出表现。 研究结果包括肢体发热、水肿和皮肤细胞因子的产生，以及表现出凉爽、 经常出现肢体萎缩并伴有新发的认知和情感缺陷。目前可用的治疗方法仅限于 有效，但在慢性期尤其无效。 单核细胞谱系细胞是对损伤的先天免疫反应的关键组成部分，无论是外周还是 “炎症”单核细胞，以及主要是卵黄囊衍生的小胶质细胞。这些细胞表达相似的受体， 然而，使他们在历史上难以区分，辨别他们个人的独特贡献是 对于理解疼痛慢性化至关重要，因为这两种细胞亚群都与 CRPS 有关。此举的目的 工作是在我们经过充分验证的 CRPS 啮齿动物模型中使用特定的遗传和药理学方法来 研究这些细胞的外周和中枢对急性期和随后的贡献 过渡到 CRPS 慢性期。这将通过多种方法的组合来完成，包括使用 两种具有转化为人类潜力的创新技术。具体来说，我们将使用高 参数质谱流式细胞术提供前所未有的功能状态全系统视角 所有主要免疫细胞亚群之间的相互作用。我们还将利用创新方法 使用正电子发射断层扫描监测疾病进展过程中神经胶质细胞的激活 配体 18F-GE-180，靶向 18 kDa 易位蛋白 TSPO，以监测小胶质细胞的激活 脊髓。这项工作的成功完成不仅将提高我们为个人量身定制治疗方案的能力 患者并合理开发新的免疫胶质细胞定向疗法，但也将提供对其实用性的深入了解 外周免疫表型和神经胶质神经影像作为可转化的诊断方法。 Tawfik 博士拥有麻醉学、疼痛医学和基础疼痛研究背景，重点关注 神经免疫。本申请中提出的详细职业发展和研究计划将提供 她成为对她的长期发展至关重要的三个领域的专家所需的资源和指导 职业目标：1）临床相关的啮齿动物疼痛模型； 2) 疼痛神经影像学高级培训 活体主题； 3）应用先进的分子遗传学工具来研究个体免疫细胞。

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.