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.

项目摘要复杂的区域疼痛综合征（CRP）是一种严重残疾的慢性疼痛形式，可以在中期发生创伤，例如骨折或轻微手术。每年美国大约有50,000个新案件每年估计有6350亿美元的医疗治疗和慢性疼痛的生产力造成贡献状况。 CRP显示了两个不同的阶段：急性相，表现出外周的突出调查结果包括肢体温暖，水肿和皮肤细胞因子的产生，以及慢性阶段，表现出很酷的，通常具有新的认知和情感缺陷的萎缩肢体。目前可用的治疗有限功效，但在慢性期尤其无效。单核细胞谱系细胞是对外围损伤的先天免疫反应的关键组成部分 “炎症性”单核细胞，并从集中用作蛋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，但是，辨别自己的个人独特贡献是对于理解疼痛回归至关重要，因为CRP已暗示了两个细胞子集。这个目的工作是在我们经过验证的CRP啮齿动物模型中使用特定的遗传和药物方法在周围和集中研究这些细胞的贡献过渡到CRP的慢性期。这将使用包括使用在内的方法组合来完成两种创新技术，有可能转化为人类。具体来说，我们将使用高参数质量细胞仪为功能状态和所有主要免疫细胞子集之间的相互作用。我们还将利用创新的方法在疾病进展过程中使用极性发射断层扫描监测神经胶质细胞的激活配体，18F-GE-180，针对18 kDa易位蛋白TSPO，以监测小胶质细胞激活脊髓。成功完成这项工作不仅会提高我们对个人量身定制治疗的能力患者并合理发展了新的免疫胶质疗法，但也将提供有关该公用事业的洞察力外周免疫表型和神经神经影像学作为可翻译的诊断方法。 Tawfik博士在麻醉，疼痛医学和基本疼痛研究中具有背景，重点是神经免疫。本申请中介绍的详细职业发展和研究计划将提供她成为长期至关重要的三个领域的专家所需的资源和精神训练职业目标：1）临床上与临床相关的啮齿动物模型； 2）疼痛神经影像学的高级培训现场主题； 3）应用晚期分子遗传学工具研究单个免疫细胞。