Small extracellular vesicles mediated signaling and pain

小细胞外囊泡介导的信号传导和疼痛

基本信息

批准号：
10685324
负责人：
Seena Ajit
金额：
$ 42.51万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685324
关键词：
Acetylation Adjuvant Adjuvant Therapy Affect Age Analgesics Anti-Inflammatory Agents Architecture Attenuated Cells Cellular Morphology Central Nervous System Circulation Communication Cytometry Deposition Dose Enhancers Epigenetic Process Future Gene Expression Goals Grant Histones Hypersensitivity Immune Immune response Immunologic Markers Immunologic Memory Immunologics Immunophenotyping In Situ In Vitro Induction of Apoptosis Injections Innate Immune Response Interleukin-10 Interleukin-6 Intrathecal Injections Lipids Macrophage Mediating Medical Memory Messenger RNA Methylation MicroRNAs Microglia Modeling Modification Mus Pain Pathologic Phenotype Physiological Play Preparation Process Prophylactic treatment Proteins Public Health RNA Transport Resolution Role Serum Signal Transduction Source Spinal Spinal Cord Spinal Ganglia Spinal cord posterior horn System TNF gene Technology Testing Therapeutic Tissue Sample Tissues Transforming Growth Factor beta United States Up-Regulation Vertebral column adaptive immune response attenuation chromatin immunoprecipitation chronic pain chronic pain management cytokine extracellular vesicles histone methylation histone methyltransferase immunoregulation improved in vivo inflammatory marker inflammatory pain inhibitor intercellular communication lipid mediator long term memory member monocyte mouse model novel pain relief prophylactic recruit response sex small molecule uptake vaccination strategy vesicle transport vesicular release

项目摘要

Abstract Chronic pain is the most prevalent, disabling, and expensive public health condition in the United States. The goal of this project is to elucidate how to harness body’s own analgesic mechanisms to provide pain relief. We propose to investigate 30-150 nm small extracellular vesicles (sEVs) that transport mRNAs, miRNAs, proteins, and lipid mediators to recipient cells via circulation. Uptake of sEVs induce gene expression changes in recipient cells and thus, sEVs play an important role in intercellular communication. We observed that sEVs from RAW 264.7 macrophage cells show therapeutic and prophylactic efficacy in a complete Freud adjuvant (CFA) mouse model of inflammatory pain. Our preliminary studies show that mouse serum derived sEVs also conferred prophylaxis when injected intrathecally in naïve recipient mice that, two weeks later, received a hind paw injection of CFA. Thus, mice that received sEVs can remember this stimulation for at least 2 weeks and show an attenuated response to CFA. How this long-term memory develop is unknown. Though chronic pain is prevalent, an immunization strategy has not yet been tested and our studies will provide the rationale and mechanistic basis for such a strategy. Here we propose to test the hypothesis that monocyte/macrophage-derived sEV subsets in serum are necessary and sufficient to attenuate inflammatory pain hypersensitivity and confer prophylaxis. We will also investigate if monocyte/macrophage sEVs recruit, or promote anti- inflammatory phenotype switching of immune cells in dorsal root ganglion and spinal cord by quantitative immunophenotyping in situ, before and after CFA treatment. Recent studies show that microglia, the resident macrophages of the central nervous system can enhance or suppress responses to a delayed secondary insult through epigenetic modifications. We hypothesize that monocyte/macrophage-derived sEVs impart epigenetic immune memory in spinal microglia of recipient mice, granting the capacity to attenuate pain from a future insult and contribute to the prophylactic effect of sEVs. The studies proposed will elucidate the role of sEVs in immune regulation and memory.

抽象的慢性疼痛是联合国最普遍，残疾和昂贵的公共健康状况国家。该项目的目的是阐明如何利用身体自己的镇痛机制提供缓解疼痛。我们建议研究30-150 nm小细胞外蔬菜（SEV）通过循环系统，将mRNA，miRNA，蛋白质和脂质介质转运到受体细胞。摄取SEV会诱导受体细胞中的基因表达变化，因此，SEV的作用在细胞间交流中的重要作用。我们观察到来自RAW 264.7的SEV 巨噬细胞在完整的弗洛伊德调整（CFA）中显示出热和预防效率炎症性疼痛的小鼠模型。我们的初步研究表明，小鼠血清得出当在胸前的小鼠中注射持智时注射时，还赋予预防后来，收到了CFA的后爪注射。那是收到Sevs的老鼠可以记住这一点刺激至少2周，并显示对CFA的衰减反应。这是如何长期的记忆发展是未知的。尽管慢性疼痛很普遍，但免疫抑制策略尚未但是经过了测试，我们的研究将为这种A提供理由和机械基础战略。在这里，我们建议测试单核细胞/巨噬细胞衍生的SEV子集的假设在血清中，需要且足以减轻炎症性疼痛过敏和会议预防。我们还将研究单核细胞/巨噬细胞SEVS募集，或促进抗背根神经节和脊髓中免疫细胞的炎症表型切换 CFA处理前后的原位定量免疫表型。最近的研究表明小胶质细胞，中枢神经系统的居民巨噬细胞可以增强或抑制通过表观遗传修饰对延迟继发损伤的反应。我们假设这一点单核细胞/巨噬细胞衍生的SEV在脊柱小胶质细胞中赋予表观遗传性免疫记忆接收者小鼠，赋予减轻未来伤害疼痛的能力，并为 SEV的预防作用。提出的研究将阐明SEV在免疫中的作用调节和记忆。