Peripheral and central immune contributions to pain chronification

项目摘要 复杂性区域疼痛综合征(CRPS)是一种严重致残的慢性疼痛，可在轻度疼痛后发生 创伤，如骨折或小手术。在美国，每年大约有5万例新病例 据估计，每年约有6350亿美元的医疗费用和慢性疼痛造成的生产力损失 条件。CRPS表现为两个不同的阶段：急性期，表现为外周突出 结果包括肢体温暖，浮肿和皮肤细胞因子的产生，以及慢性期表现出凉爽， 常为肢体萎缩，伴有新的认知和情感缺陷。目前可用的治疗方法仅限于 有效，但在慢性期尤其无效。 单核细胞系细胞是损伤的先天免疫反应的关键组成部分，在外周 “炎性”单核细胞，中央为卵黄囊来源的小胶质细胞。这些细胞表达相似的受体， 然而，使他们在历史上很难区分的是，辨别他们各自独特的贡献 对于理解疼痛的时序化至关重要，因为两个细胞亚群都与CRPS有关。这样做的目的是 我们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 研究这些细胞在周围和中央对急性期和随后的 过渡到CRPS慢性期。这将使用多种方法来完成，包括使用 两种有可能翻译成人类的创新技术。具体来说，我们将使用高- 参数质量细胞术提供前所未有的全系统功能状态和 所有主要免疫细胞亚群之间的相互作用。我们还将利用创新的方法 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 18F-Ge-180，靶向18 kDa转位蛋白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做治疗的能力 合理地开发新的免疫-神经胶质导向疗法，但也将提供对其效用的洞察 外周免疫表型和神经胶质成像作为可翻译的诊断方法。 陶菲克博士拥有麻醉学、疼痛医学和基础疼痛研究方面的背景，重点是 神经免疫力。此申请表中提供的详细职业发展和研究计划将提供 她成为三个领域的专家所需的资源和指导对她的长期职业生涯至关重要 职业目标：1)临床相关的疼痛啮齿动物模型；2)高级培训疼痛的神经成像 活体受试者；以及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.