MICA: Towards targeted treatment for complex regional pain syndrome through determination of the underlying molecular mechanisms

MICA：通过确定潜在的分子机制来靶向治疗复杂的区域疼痛综合征

• 批准号: MR/W027240/1
• 负责人: Clare Bryant
• 金额: $ 49.28万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW027240%2F1
• 关键词: MICA; Towards; targeted; treatment; complex

Complex regional pain syndrome (CRPS) is a chronic pain condition that can occur after an injury, such as a fracture and results in localised pain and swelling. CRPS spontaneously resolves within a year in 20-30% of cases, but after this time it becomes chronic and rarely improves. Treatment options for CRPS patients, as with many other forms of chronic pain, are very limited, untargeted, and often have significant side effects. It is, therefore, important to understand why CRPS develops and the underlying mechanisms involved in order to try and develop more effective drugs targeting pain and inflammation and improve lives of those living with CRPS.We can often gain insight into why a disease develops by looking at changes found in genes (mutations), which in turn helps design new drugs, such as pain killers (analgesics). For example, changes in a gene called nerve growth factor, were found in a family unable to feel pain (inherited as a very rare disease), and this led to the discovery of a new class of analgesics that is particularly helpful against arthritic pain. We wanted to see if patients with CRPS had mutations in their genes, compared to non-sufferers, which could alter their susceptibility to the condition. We found that CRPS patients were more likely to have mutations in four genes compared to people without CRPS. Each of these mutations was hypothesised to cause alterations of protein function. We, and others, have shown these four genes are expressed in monocytes and/or macrophages (cells that engulf foreign particles and cause inflammation). Importantly, all four genes are linked to the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammatory pathway that senses foreign particles and removes them by causing release of inflammatory molecules and cell death. These data suggest that the NLRP3 inflammasome pathway is likely to be important in the pathology of CRPS. In this proposal we will investigate how the CRPS-mutated genes affect the activity of the NLRP3 inflammasome. In order to do this, we will introduce the gene mutations into a human monocyte cell line (THP-1 cells). Next, we will determine if these mutations alter the activity of the NLRP3 inflammasome by measuring the production of inflammatory molecules and cell death in THP-1 cells. We will validate the THP-1 model by measuring inflammasome activity in cells from healthy individuals with the CRPS-associated mutations. Our next step will be to determine how these changes in NLRP3 inflammasome activity influence pain neuron activation as a method to model the excessive pain seen in CRPS. Lastly, we will test how NLRP3 modulators affect pain and inflammation in order to translate our findings towards the development of new drugs for CRPS. We anticipate our research will lead to the identification of a new class of non-addictive pain-killers that will reduce inflammation and pain to stop the chronic stage of CRPS from developing. This would have very significant effects on pain management, inflammation and the depression, morbidity and mortality that are a consequence of prolonged severe pain.

复杂的区域疼痛综合征（CRP）是一种慢性疼痛疾病，可能在损伤后发生，例如骨折并导致局部疼痛和肿胀。 CRP在20-30％的病例中自发消退，但此后它变得慢性，很少有所改善。与许多其他形式的慢性疼痛一样，CRPS患者的治疗选择非常有限，未靶向，并且通常具有显着的副作用。因此，重要的是要了解为什么CRP会发展以及涉及的潜在机制，以尝试开发针对疼痛和炎症的更有效的药物，并改善CRP的人的生活。我们经常可以深入了解疾病在基因中发现的变化（突变）的变化，这反过来又有助于设计新药，例如疼痛杀手（例如疼痛杀手）（肛门型杀手）。例如，在一个无法感到疼痛的家族中发现了一种称为神经生长因子的基因的变化（作为一种非常罕见的疾病），这导致发现了一种新的镇痛药，这些镇痛药特别有用，以防止关节炎疼痛。我们想看看CRP患者的基因突变是否与非助手相比，这可能会改变其对病情的敏感性。我们发现，与没有CRP的人相比，CRPS患者更有可能在四个基因中发生突变。假设这些突变中的每一个都会导致蛋白质功能的改变。我们和其他人表明，这四个基因在单核细胞和/或巨噬细胞（吞噬异物颗粒并引起炎症的细胞）中表达。重要的是，所有四个基因均与含含蛋白质的蛋白3（NLRP3）炎症途径的点，LRR和吡啶结构域的炎症途径相关，该途径会感受到异物并通过释放炎症分子和细胞死亡来清除它们。这些数据表明，NLRP3炎性途径在CRP的病理中可能很重要。在该提案中，我们将研究CRPS突变的基因如何影响NLRP3炎症体的活性。为此，我们将将基因突变引入人类单核细胞系（THP-1细胞）。接下来，我们将通过测量THP-1细胞中炎症分子的产生和细胞死亡的产生来确定这些突变是否改变了NLRP3炎症体的活性。我们将通过测量来自具有CRPS相关突变的健康个体的细胞中的炎性体活性来验证THP-1模型。我们的下一步将是确定NLRP3炎性体活动中的这些变化如何影响疼痛神经元激活，以模拟CRP中看到的过度疼痛。最后，我们将测试NLRP3调节剂如何影响疼痛和炎症，以将我们的发现转化为开发CRP的新药。我们预计我们的研究将导致鉴定出一类新的非成瘾性止痛药，这些止痛药将减少炎症和疼痛，从而阻止CRP的慢性阶段发展。这将对疼痛管理，炎症以及抑郁症，发病率和死亡率产生非常重要的影响，这是长期剧烈疼痛的结果。