Inflammasome Activation in Complex Regional Pain Syndrome

描述(申请人提供)：复杂性区域疼痛综合征I型(CRPS I)是一种常见的胫骨和桡骨远端骨折和肢体手术的后遗症，尽管即使在轻微受伤后也可以发生。疼痛是该综合征的突出特征，CRPS环境中的残疾是非常常见的。最近，我们的团队描述了一种胫骨骨折模型，其主要特征是CRPS I包括慢性水肿、痛觉异常、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，可用的临床治疗效果有限。皮肤固有免疫系统的激活启动了支持这种慢性病的一连串变化。这项研究方案概述了一套垂直整合的实验，所有实验都集中在中心假设，即角质形成细胞炎症体的神经激活是产生IL-12所必需的，下游介质如神经生长因子(NGF)，并最终在我们的啮齿动物模型中发展类似CRPS的特征。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肾上腺素能受体激动剂刺激炎症体关键成分的产生以及caspase-1激活导致细胞因子产生的假说。2.我们将验证一种假设，即炎症小体激活发生在骨折后，并且是小鼠胫骨骨折后CRPS样综合征表达所必需的。3.我们将验证这样一种假设，即骨折后皮肤中炎性小体的激活需要完整的周围神经系统信号，而这种激活又是CRPS相关生物标志物的表达以及水肿、温暖和伤害性敏感化所必需的。这些实验将同时使用细胞培养和整体动物实验。我们将检测CRPS的基因表达、介体水平、酶活性和行为指标。短期内，我们将完善神经-皮肤信号模型，因为它支持CRPS I的特定维度。长期而言，我们希望将这些发现转化为涉及CRPS I患者的临床试验，这将因研究团队的临床定位和针对炎症调节的药物的出现而成为可能。

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.