Peripheral and central immune contributions to pain chronification

外周和中枢免疫对疼痛慢性化的贡献

基本信息

批准号：
9890013
负责人：
Vivianne L Tawfik
金额：
$ 10.91万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890013
关键词：
Acute Affect Anesthesiology Anxiety Astrocytes Atrophic Award Biology Cell Lineage Cells Chronic Chronic Phase Cognitive Complex Regional Pain Syndromes Cytometry Data Diagnostic Disease Disease Progression Edema Emotional Exhibits Flow Cytometry Fracture Genetic Goals HMGB1 gene ITGAM gene Immune Immunohistochemistry Immunomodulators Individual Inflammatory Injury Innate Immune Response Knowledge Ligands Limb structure Measures Medical Medicine Memory Mentorship Microglia Minor Minor Surgical Procedures Modeling Molecular Molecular Genetics Monitor Neuraxis Neurocognitive Neurocognitive Deficit Neuroglia Neuroimmune Neuronal Injury Pain Pain Research Pattern Peripheral Persistent pain Pharmacology Phase Phenotype Physicians Population Positron-Emission Tomography Posture Process Production Productivity Proteins Refractory Resources Rodent Rodent Model Scientist Signal Transduction Skin Spinal Cord System TLR4 gene Techniques Temperature Testing Tibial Fractures Time Training Transgenic Mice Trauma United States Widespread Disease Work Yolk Sac allodynia base behavioral outcome career career development cellular targeting chronic pain chronic painful condition clinically relevant cognitive change cost estimate cytokine defined contribution disability disabling disease experimental study field study follow-up functional status gait examination glial activation improved in vivo individual patient individualized medicine inflammatory milieu inhibitor/antagonist innovation insight knock-down molecular targeted therapies monocyte neuroimaging neurotransmission novel pain model receptor research and development response to injury tool translation to humans

项目摘要

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.

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。骨折或小手术等外伤美国每年大约有 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 CRPS 表现出两个不同的阶段：急性期，表现出外周病变的突出。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有限。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，以及卵黄囊衍生的小胶质细胞，这些细胞表达类似的受体，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 相关。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对急性期和随后的外周和中枢的贡献过渡到 CRPS 的慢性阶段这将通过多种方法来完成，包括使用具体来说，我们将使用两种具有转化为人类潜力的创新技术。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成功完成这项工作不仅将提高我们为个人量身定制治疗方法的能力。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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microglial Modulation as a Target for Chronic Pain: From the Bench to the Bedside and Back.

小胶质细胞调节作为慢性疼痛的目标：从工作台到床边再到背部。

DOI：
10.1213/ane.0000000000004033
发表时间：
2019-04-01
期刊：
Anesthesia and analgesia
影响因子：
5.7
作者：
Elena S. Haight;Thomas E. Forman;Stephanie Cordonnier;M. James;V. Tawfik
通讯作者：
V. Tawfik

Chronic Pain Management in the Elderly.

老年人的慢性疼痛管理。

DOI：
10.1016/j.anclin.2019.04.012
发表时间：
2019-09-01
期刊：
Anesthesiology clinics
影响因子：
0
作者：
Josianna V. Schwan;J. Sclafani;V. Tawfik
通讯作者：
V. Tawfik

Longitudinal translocator protein-18 kDa-positron emission tomography imaging of peripheral and central myeloid cells in a mouse model of complex regional pain syndrome.

复杂区域疼痛综合征小鼠模型中外周和中央骨髓细胞的纵向易位蛋白 18 kDa 正电子发射断层扫描成像。

DOI：
发表时间：
2019
期刊：
影响因子：
7.4
作者：
Cropper, Haley C;Johnson, Emily M;Haight, Elena S;Cordonnier, Stephanie A;Chaney, Aisling M;Forman, Thomas E;Biswal, Anjali;Stevens, Marc Y;James, Michelle L;Tawfik, Vivianne L
通讯作者：
Tawfik, Vivianne L

Of mice, microglia, and (wo)men: a case series and mechanistic investigation of hydroxychloroquine for complex regional pain syndrome.

小鼠、小胶质细胞和（女性）男性：羟氯喹治疗复杂区域疼痛综合征的病例系列和机制研究。