Exosome-mediated signaling in neuropathic pain

神经病理性疼痛中外切体介导的信号转导 由神经系统损伤或故障引起的慢性神经病理性疼痛是极其严重的 很难治疗。与生理性或急性疼痛不同，在受损的神经或 组织愈合，神经性疼痛可导致痛觉过敏(非痛性刺激引起的疼痛)和 痛觉过敏(对疼痛高度敏感)。急性与慢性的深刻区别 疼痛表明，疼痛是高度可塑性的分子和回路相互作用的结果。 Exosome是30-100 nm的囊泡，携带mRNAs、miRNAs、蛋白质和脂质介质 受体细胞通过循环。细胞使用这些小泡与相邻的和 遥远的手机。存在于这些囊泡表面的分子使它们能够靶向 受体细胞。胞外体的含量因来源和生理原因而异。 释放它们的细胞的条件，以及已知改变外切体的疾病状态 组成。但是，并不是父单元格中的所有内容都合并到 Exosome，这表明这一调节良好的过程是通过信号提示动态改变的。 外切体摄取导致受体细胞基因表达的调节，并代表了一种新的 蜂窝通讯的机制。到目前为止，还没有研究调查在 神经病理性疼痛状态下的外切体组成、功能和信号机制。我们的 神经病理性疼痛小鼠模型血清外切体的初步数据 术后几周，与假手术组相比，显示出明显的外体miRNA和蛋白质特征 控制力。我们推测，神经损伤后外体成分的变化 它们具有致痛作用，有助于维持慢性神经病理性疼痛。在体外使用， 体外和体内方法，我们将研究摄取 神经损伤模型小鼠血清外显体与假手术对照小鼠的比较。差异在于 受体细胞对胞外体的摄取，对神经元、星形胶质细胞或胶质细胞的偏好， 促炎症介质，外切体诱导的热和机械超敏反应 将研究通过抑制外切体释放来逆转超敏反应。这些研究将 提供对慢性慢性病下外切体释放导致的新的信号机制的见解 神经病理性疼痛及其在维持疼痛中的作用。功能性质的阐明 外切体有助于开发新的治疗干预策略来治疗慢性阻塞性肺疾病 疼痛。

Exosome-mediated signaling in neuropathic pain Chronic neuropathic pain resulting from injury or malfunction of the nervous system is extremely difficult to treat. Unlike physiological or acute pain, where pain ceases after the damaged nerves or tissue heal, neuropathic pain can result in allodynia (pain from a non-painful stimulus) and hyperalgesia (heightened sensitivity to pain). The profound differences between acute and chronic pain indicate that pain results from the engagement of highly plastic molecules and circuits. Exosomes are 30-100 nm vesicles that carry mRNAs, miRNAs, proteins, and lipid mediators to recipient cells via circulation. Cells use these vesicles to communicate with both adjacent and distant cells. The molecules present on the surface of these vesicles enable them to target recipient cells. The exosomal contents vary depending on the source and the physiological conditions of cells releasing them, as well as on disease states that are known to alter exosome composition. However, not everything that is present in the parent cell is incorporated into the exosomes, suggesting that this well-regulated process is dynamically altered by signaling cues. Exosome uptake results in modulation of gene expression in recipient cells and represents a novel mechanism of cellular communication. There are no studies to date investigating alterations in exosome composition, function, and signaling mechanisms in a neuropathic pain state. Our preliminary data characterizing exosomes in serum from a mouse model of neuropathic pain four weeks after surgery showed a distinct exosomal miRNA and protein signature compared to sham control. We hypothesize that alterations in exosomal composition following nerve injury render them pronociceptive and contribute to the maintenance of chronic neuropathic pain. Using in vitro, ex vivo and in vivo approaches, we will investigate gene expression changes induced by uptake of exosomes from the serum of nerve injury model compared to sham control mice. Differences in exosomal uptake by recipient cells, preference for neurons, astrocytes or glia, alterations in proinflammatory mediators, thermal and mechanical hypersensitivity induced by exosomes and reversal of hypersensitivity by inhibition of exosome release will be investigated. These studies will provide insights on novel signaling mechanisms resulting from exosome release under chronic neuropathic pain and their role in the maintenance of pain. Elucidation of functional properties of exosomes can be beneficial in developing novel therapeutic intervention strategies to treat chronic pain.