Exosome-mediated signaling in neuropathic pain

外泌体介导的神经病理性疼痛信号传导

• 批准号: 10183345
• 负责人: Seena Ajit
• 金额: $ 36.38万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183345
• 关键词: Acute Pain; Adhesions; Animals; Antigen-Presenting Cells; Astrocytes; Attenuated; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Cell Nucleus; Cells; Chronic; Communication; Complement 5a; Complement Activation; Cues; Data; Disease; Distant; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Homing; Human; Hyperalgesia; Hypersensitivity; Immune; Impairment; In Vitro; Incubated; Inflammation; Injury; Intercellular adhesion molecule 1; Intervention; Knock-out; Knockout Mice; Leukocytes; Maintenance; Mechanics; Mediating; Mediator of activation protein; Membrane Proteins; Messenger RNA; MicroRNAs; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Nervous system structure; Neuroglia; Neurons; Neuropathy; Operative Surgical Procedures; Pain; Painless; Parents; Pathogenicity; Pharmacology; Physiological; Posterior Horn Cells; Process; Property; Proteins; Proteomics; RNA Sequences; Role; Serum; Signal Transduction; Slice; Source; Spinal Cord; Spinal Ganglia; Spinal cord posterior horn; Stimulus; Surface; System; Testing; Thermal Hyperalgesias; Time; Tissues; Vesicle; Wild Type Mouse; allodynia; chronic neuropathic pain; chronic pain; conditioned place preference; cytokine; differential expression; exosome; healing; immunoregulation; in vivo; inhibitor/antagonist; insight; lipid mediator; migration; monocyte; mouse model; nerve damage; nerve injury; novel; novel therapeutic intervention; painful neuropathy; preference; protein expression; recruit; small hairpin RNA; spared nerve; transcriptome sequencing; uptake

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.

外泌体介导的神经病理性疼痛信号转导 由神经系统损伤或功能障碍引起的慢性神经性疼痛是极其严重的。 与生理性或急性疼痛不同，疼痛在神经受损后停止， 组织愈合后，神经性疼痛可导致异常性疼痛（来自非疼痛刺激的疼痛）， 痛觉过敏（对疼痛的敏感性增强）。急性和慢性之间的深刻差异 疼痛表明疼痛是由高度可塑的分子和电路的接合引起的。 外泌体是30-100 nm的囊泡，其携带mRNA、miRNA、蛋白质和脂质介质， 受体细胞通过循环。细胞利用这些囊泡与相邻的细胞和 遥远的细胞这些囊泡表面的分子使它们能够靶向 受体细胞外泌体的含量根据来源和生理条件而变化。 细胞释放它们的条件，以及已知改变外泌体的疾病状态 混合物.然而，并不是所有存在于亲本细胞中的东西都被整合到亲本细胞中。 外泌体，表明这一良好的调节过程是动态改变的信号线索。 外泌体摄取导致受体细胞中基因表达的调节，并代表了一种新的 蜂窝通信的机制。迄今为止，没有研究调查 外泌体组成、功能和神经性疼痛状态中的信号传导机制。我们 表征来自神经性疼痛小鼠模型的血清中的外来体的初步数据 与假手术组相比，手术后24周显示出明显的外泌体miRNA和蛋白质特征 控制我们假设神经损伤后外泌体组成的改变使 它们是亲伤害感受性的，并有助于维持慢性神经性疼痛。使用体外， 离体和体内的方法，我们将研究基因表达的变化引起的摄取 与假手术对照小鼠相比，来自神经损伤模型的血清的外泌体。差异 受体细胞的外泌体摄取，对神经元、星形胶质细胞或神经胶质细胞的偏好， 促炎介质，由外来体诱导的热和机械超敏反应， 将研究通过抑制外来体释放来逆转超敏反应。这些研究将 提供了对慢性炎症下外泌体释放引起的新型信号传导机制的见解。 神经性疼痛及其在维持疼痛中的作用。功能特性的阐明 外泌体可以有益于开发新的治疗性干预策略以治疗慢性炎症。 痛苦

项目成果

In Vitro Validation of miRNA-Mediated Gene Expression Linked to Drug Metabolism.

与药物代谢相关的miRNA介导的基因表达的体外验证。

• DOI: 10.1002/cpph.30
• 发表时间: 2017-12-20
• 期刊: Current protocols in pharmacology
• 作者: Shenoda BB;Ramanathan S;Ajit SK
• 通讯作者: Ajit SK

Complex regional pain syndrome - phenotypic characteristics and potential biomarkers.

• DOI: 10.1038/nrneurol.2018.20
• 发表时间: 2018-05
• 期刊: Nature reviews. Neurology
• 作者: Birklein F;Ajit SK;Goebel A;Perez RSGM;Sommer C
• 通讯作者: Sommer C

Xist attenuates acute inflammatory response by female cells.

• DOI: 10.1007/s00018-020-03500-3
• 发表时间: 2021-01
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Shenoda BB;Ramanathan S;Gupta R;Tian Y;Jean-Toussaint R;Alexander GM;Addya S;Somarowthu S;Sacan A;Ajit SK
• 通讯作者: Ajit SK

Therapeutic and prophylactic effects of macrophage-derived small extracellular vesicles in the attenuation of inflammatory pain.

• DOI: 10.1016/j.bbi.2021.02.005
• 发表时间: 2021-05
• 期刊: Brain, behavior, and immunity
• 作者: Jean-Toussaint R;Lin Z;Tian Y;Gupta R;Pande R;Luo X;Hu H;Sacan A;Ajit SK
• 通讯作者: Ajit SK

miR-106b-25 Dysregulation in Complex Regional Pain Syndrome Contributes to T Cell Dysfunction.

复杂区域疼痛综合征中的 miR-106b-25 失调导致 T 细胞功能障碍。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Wickman,Jason;Shenoda,Botros;VanDuyne,Rachel;Klase,Zachary;Ajit,Seena
• 通讯作者: Ajit,Seena