Peripheral and central immune contributions to pain chronification

项目摘要 复杂区域疼痛综合征（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。美国每年大约有5万例新病例， 据估计，慢性疼痛每年造成6350亿美元的医疗费用和生产力损失。 条件CRPS表现出两个不同的阶段：急性期，表现出周围神经系统的突出， 发现包括肢体温暖、水肿和皮肤细胞因子产生，以及慢性阶段表现出凉爽， 通常是萎缩的肢体，伴有新发的认知和情感缺陷。目前可用的治疗方法有限， 但在慢性期尤其无效。 单核细胞系细胞是对损伤的先天性免疫应答的关键组分， “炎性”单核细胞，和中央，作为卵黄囊衍生的小胶质细胞。这些细胞表达类似的受体， 这使得他们在历史上很难区分，然而，辨别他们的个人，独特的贡献， 这对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。的目的 我们的工作是在我们经过充分验证的啮齿动物CRPS模型中使用特定的遗传和药理学方法， 研究这些细胞在外周和中枢对急性期和随后的 向CRPS慢性期的过渡。这将使用多种方法的组合来完成，包括使用 两种创新技术的结合体，有可能转化为人类。具体来说，我们将使用高- 参数质谱细胞术，以提供前所未有的系统范围内的功能状态的观点， 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的神经胶质细胞活化 配体，18F-GE-180，靶向18 kDa转运蛋白，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定制治疗的能力， 患者和合理开发新的免疫神经胶质细胞定向疗法，但也将提供洞察效用 外周免疫表型和胶质神经成像作为可翻译的诊断方法。 博士陶菲克有麻醉学，疼痛医学和基础疼痛研究的背景，重点是 神经免疫详细的职业发展和研究计划在此应用程序中提出将提供 所需的资源和指导，她成为一个专家在三个领域的关键，她的长期 职业目标：1）临床相关的啮齿动物疼痛模型; 2）疼痛神经成像的高级培训， 活体受试者; 3）应用先进的分子遗传学工具研究个体免疫细胞。

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.