MICA: Exosomes and microRNAs regulate neuro-immune interactions in chronic pain

神经损伤或炎性关节炎后的慢性疼痛是一种使人衰弱的病症，其中疼痛经历持续很长时间。疼痛是神经损伤后或类风湿性关节炎（RA）中的持续症状，即使在用药物抑制关节疾病后疼痛仍然存在。慢性疼痛很难治疗，目前的药物相对无效，而且往往有显着的副作用。因此，更好地了解持续性疼痛的机制可以为如何预防或减轻慢性疼痛带来新的想法，并促进新药的开发。我们在研究中使用小鼠，因为它们在关节炎和周围神经病变（PN）模型中也表现出后爪疼痛相关行为，持续数周。疼痛是RA和PN的标志，其中血细胞进入关节和受伤的神经并产生激活疼痛神经的因子：这些神经将疼痛信号从关节或受伤的神经传递到脊髓，然后到达感觉疼痛的大脑。我们发现，血液来源的细胞不仅存在于关节或受伤的神经中，而且还存在于关节外的疼痛细胞周围，并且在一种称为背根神经节（DRG）的结构中受伤的神经。在远离肿胀关节和损伤神经的DRG部位，血细胞影响疼痛神经，促进疼痛感觉。在这些血液来源的细胞中，我们已经确定了新的靶点，可以用来调节疼痛活动，并可能构成治疗持续性疼痛的新方法。这些新靶点是小股遗传物质，在DRG的疼痛细胞中产生，并包装在小的微观结构中。疼痛细胞将这些颗粒传递给血液来源的细胞，通过增加增加疼痛敏感性的化学物质的产生来调节它们的活性。我们已经找到了一种新的方法来靶向血液来源的细胞中的这种遗传物质。在这个项目中，我们将使用各种方法来评估血液来源的细胞在疼痛动物模型中的活性，并确定这种活性对携带疼痛信号的神经细胞的影响。然后，我们将测量当血液来源的细胞中的特定活动被阻断时的疼痛读数。这项研究将使我们能够确定血液来源细胞中靶点治疗持续性疼痛的治疗潜力：神经损伤后的慢性疼痛或炎症性关节炎都将被研究。我们研究的最终目的是提供新的信息，这将有助于设计新的止痛药物，从而使慢性疼痛治疗更有效，以最终改善患者的生活质量。

Chronic pain after nerve damage or inflammatory arthritis is a debilitating condition in which the pain experience persists for long time. Pain is a persistent symptom following injury to nerve or in rheumatoid arthritis (RA) whereby pain remains even after suppression of joint disease with medicines. Chronic pain is difficult to treat, with current drugs being relatively ineffective and often having significant side effects. Therefore, a better understanding of the mechanisms responsible for persistence of pain can bring new ideas on how to prevent or attenuate chronic pain and facilitate the development of new medicines. We use mice in our studies as they also demonstrate pain-related behaviour in their hind paws that persists for several weeks in models of joint arthritis and peripheral neuropathy (PN). Pain is a sign of both RA and PN, where blood cells enter the joint and the injured nerve and produce factors that activate pain nerves: these nerves carry pain signals from the joint or injured nerve to the spinal cord on their way to the brain where pain is felt. We discovered that blood-derived cells are not only in the joint or the injured nerve, but they are also around pain cells outside the joint and injured nerve in a structure that is called dorsal root ganglia (DRG). At this DRG site, far away from the swollen joint and injured nerve, blood-derived cell influence pain nerves and favour pain sensation. In these blood-derived cells we have identified new targets that can be exploited to regulate pain activity and may constitute novel approaches to treating persistent pain. These new targets are small strands of genetic material, produced in the pain cells of the DRG and packaged in small microstructures. Pain cells handover these particles to blood-derived cells to regulate their activity by increasing production of chemicals that increase pain sensitivity. We have identified a new way to target this genetic material within blood-derived cells.In this project, we will use a variety of methods to assess the activity of blood-derived cells in animal models of pain, and determine the effects of this activity on the nerve cells that carry pain signals. We will then measure readouts of pain when specific activity in blood-derived cells has been either blocked. This study will allow us to determine the therapeutic potential of targets in blood-derived cells for the treatment of persistent pain: both chronic pain after nerve damage or inflammatory arthritis will be studied.The ultimate aim of our research is to provide new information that will help in the design of novel pain-relieving medicines, thus allowing chronic pain treatments to be more effective to ultimately improve the quality of life of patients.