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

神经损伤或炎症性关节炎后的慢性疼痛是一种持续很长时间的疼痛体验，使人虚弱。疼痛是神经损伤或类风湿性关节炎(RA)后的一种持续性症状，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，而且往往有显著的副作用。因此，更好地了解疼痛持续的机制可以为如何预防或减轻慢性疼痛带来新的思路，并促进新药的开发。我们在我们的研究中使用小鼠，因为它们也在关节关节炎和周围神经病(PN)模型中展示了持续数周的后爪疼痛相关行为。疼痛是RA和PN的症状，血细胞进入关节和受伤的神经，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，在到达感受疼痛的大脑的途中。我们发现，血液来源的细胞不仅存在于关节或损伤的神经中，而且还存在于关节外的疼痛细胞和损伤的神经中，这种结构被称为背根节(DRG)。在这个背根节部位，远离肿胀的关节和受损的神经，血源性细胞影响疼痛神经，有利于痛感。在这些血源性细胞中，我们已经确定了可用于调节疼痛活动的新靶点，并可能构成治疗持续性疼痛的新方法。这些新的靶点是遗传物质的小链，在背根节的疼痛细胞中产生，并被包装在微小的微结构中。疼痛细胞将这些颗粒移交给血液来源的细胞，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动。我们已经确定了一种在血液来源的细胞中靶向这种遗传物质的新方法。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，并确定这种活动对携带疼痛信号的神经细胞的影响。然后，当血液来源的细胞的特定活动被阻断时，我们将测量疼痛读数。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潜力：将研究神经损伤后的慢性疼痛或炎症性关节炎。我们研究的最终目的是提供新的信息，帮助设计新的止痛药物，从而使慢性疼痛治疗更有效，最终提高患者的生活质量。

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.