Inflammasome Activation in Complex Regional Pain Syndrome

复杂区域疼痛综合征中的炎症小体激活

• 批准号: 8517225
• 负责人: DAVID J. CLARK
• 金额: $ 29.34万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517225
• 关键词: Adrenergic Agents; Adrenergic Agonists; Agonist; Animal Experiments; Animals; Behavioral; Biochemical; Biological Markers; CASP1 gene; Calcitonin Gene-Related Peptide; Capsaicin; Caspase-1; Catecholamines; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Clinical Treatment; Clinical Trials; Complex Regional Pain Syndromes; Cutaneous; Development; Dimensions; Distal; Dopamine; Edema; Electric Stimulation; Epithelial; Exhibits; Fiber; Fracture; Gene Deletion; Gene Expression; Immunity; Inflammation; Inflammatory; Injury; Interleukin-12; Lesion; Limb structure; MEKs; Maintenance; Measurement; Measures; Mediating; Mediator of activation protein; Minor; Modeling; Molecular; Mus; Nerve; Nerve Growth Factors; Nervous system structure; Neurologic; Neurons; Neuropeptide Receptor; Neuropeptides; Nociception; Operative Surgical Procedures; Osteoporosis; Pain; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Pharmacologic Substance; Population; Production; Radius Fractures; Rattus; Reflex Sympathetic Dystrophy; Regulation; Research Proposals; Rodent Model; Role; Signal Transduction; Skin; Small Interfering RNA; Source; Substance P; Sympathetic Nervous System; Syndrome; System; Testing; Tibial Fractures; Translating; adrenergic; allodynia; autocrine; base; beta-2 Adrenergic Receptors; chronic pain; cytokine; disability; human data; human disease; indexing; keratinocyte; neuromechanism; neuroregulation; novel; novel strategies; novel therapeutics; relating to nervous system; research study; response; sciatic nerve; social stigma; tibia; tool

DESCRIPTION (provided by applicant): Complex Regional Pain Syndrome Type I (CRPS I) is a frequent sequela of distal tibia and radius fractures and limb surgery though it can occur even after minor injuries. Pain is a prominent feature of this syndrome, and disability in the setting of CRPS is very common. Recently our group described a tibia fracture model that exhibits the principal stigmata of CRPS I including chronic edema, allodynia, epidermal thickening, keratinocyte proliferation and periarticular osteoporosis. Unfortunately, the mechanisms supporting these changes remain highly enigmatic, and available clinical treatments have limited efficacy. Activation of the innate system of immunity in skin initiates the cascade of changes supporting this chronic disease. This research proposal outlines a vertically integrated set of experiments all focused on the central hypothesis that neural activation of keratinocyte inflammasomes is required for the production of IL-12, downstream mediators such as nerve growth factor (NGF), and ultimately the development of CRPS-like features in our rodent model. The project's specific aims are as follows: 1. We will test the hypothesis that substance P (SP), calcitonin gene related peptide (CGRP) and beta 2 adrenergic receptor agonists stimulate the production of key inflammasome components, and the activation of caspase-1 resulting in enhanced cytokine production. 2. We will test the hypothesis that inflammasome activation occurs after fracture, and is required for expression of the CRPS-like syndrome after tibial fracture in mice. 3. We will test the hypothesis that intact peripheral nervous system signaling is required for the activation of inflammasomes in skin after fracture, and that this activation is, in turn, required for the expression of CRPS-related biomarkers as well as edema, warmth and nociceptive sensitization. These experiments will use both cell culture and whole animal experiments. We will measure gene expression, mediator levels, enzymatic activity and behavioral indices of CRPS. In the short term we will refine the model of neuro-cutaneous signaling as it supports specific dimensions of CRPS I. In the longer run we hope to translate these findings into clinical trials involving CRPS I patients which will be made possible by the clinical orientation of the investigative team and the advent of pharmaceutical agents targeted at the regulation of inflammation.

描述（由申请人提供）： I 型复杂区域疼痛综合征 (CRPS I) 是胫骨远端和桡骨骨折以及肢体手术的常见后遗症，尽管即使在轻伤后也可能发生。疼痛是该综合征的一个显着特征，CRPS 中的残疾也很常见。最近，我们小组描述了一种胫骨骨折模型，该模型表现出 CRPS I 的主要特征，包括慢性水肿、异常性疼痛、表皮增厚、角质形成细胞增殖和关节周围骨质疏松。不幸的是，支持这些变化的机制仍然非常神秘，现有的临床治疗效果有限。皮肤先天免疫系统的激活引发了支持这种慢性疾病的一系列变化。该研究提案概述了一组垂直整合的实验，全部集中在一个中心假设上，即角质形成细胞炎症小体的神经激活是产生 IL-12、神经生长因子 (NGF) 等下游介质以及最终 CRPS-的发展所必需的。就像我们的啮齿动物模型中的特征一样。该项目的具体目标如下： 1. 我们将检验P物质（SP）、降钙素基因相关肽（CGRP）和β2肾上腺素受体激动剂刺激关键炎症小体成分的产生以及caspase-1激活的假设导致细胞因子的产生增强。 2. 我们将检验以下假设：骨折后发生炎症小体激活，并且是小鼠胫骨骨折后 CRPS 样综合征表达所必需的。 3. 我们将检验以下假设：骨折后皮肤炎症小体的激活需要完整的周围神经系统信号传导，而这种激活反过来又是 CRPS 相关生物标志物以及水肿、温暖和炎症的表达所必需的。伤害性敏化。这些实验将使用细胞培养和整体动物实验。我们将测量 CRPS 的基因表达、介质水平、酶活性和行为指数。短期内，我们将完善神经皮肤信号传导模型，因为它支持 CRPS I 的特定维度。从长远来看，我们希望将这些发现转化为涉及 CRPS I 患者的临床试验，这将通过临床定位而成为可能。研究小组和针对炎症调节的药剂的出现。