Targeting Schwann cell exosomes for treating neuropathic pain

靶向雪旺细胞外泌体治疗神经性疼痛

• 批准号: 10222806
• 负责人: WENDY M. CAMPANA
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222806
• 关键词: Address; Affect; Afferent Neurons; American; Biology; Blood; Calcium Signaling; Cells; Chronic; Clinical; Cognitive; Communication; Data; Dependence; Development; Emergency Situation; Environment; Exposure to; Foundations; General Population; Goals; Growth; Growth Cones; In Vitro; Injury; Ligation; Link; Maintenance; Measures; Membrane; Methods; MicroRNAs; Nerve; Nerve Regeneration; Nervous System Physiology; Nervous System Trauma; Neurites; Neuroglia; Neurons; Neuropathy; Nucleic Acids; Outcome; PC12 Cells; Pain; Pain Disorder; Pain management; Pathogenesis; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Pharmacology; Phenotype; Physiology; Plasma; Play; Process; Property; Proteins; Protocols documentation; RNA; Rattus; Recovery; Refractory; Refuse Disposal; Regenerative capacity; Regenerative research; Research; Research Design; Research Project Grants; Research Proposals; Risk; Rodent; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Small RNA; Source; Spinal; Stream; Surface; System; Technology; Testing; Therapeutic; Thermal Hyperalgesias; Trauma; Untranslated RNA; Veterans; Work; alternative treatment; base; behavioral study; biomaterial compatibility; chronic neuropathic pain; chronic pain; chronic pain management; combat injury; cost; debilitating pain; dorsal horn; exosome; experimental study; extracellular vesicles; first responder; high risk; improved; in vivo; inhibitor; injured; innovation; limb injury; miRNA expression profiling; molecular marker; nano-string; nanovesicle; novel; opioid epidemic; opioid therapy; pain outcome; pain processing; pain signal; painful neuropathy; prevent; programs; regeneration following injury; rehabilitation research; repaired; research and development; research vision; response; response to injury; service programs; severe injury; transcriptome; wounded soldier

It is increasingly evident that Schwann cells (SCs) in the peripheral nervous system (PNS) function as a unit with neurons to regulate sensory function. When the PNS is injured in trauma, SCs become activated for repair. This involves dramatic phenotypic transformation. If this process is abnormal or inhibited, peripheral nerve injury can result in chronic debilitating pain, a problem observed in the general population, including numerous Veterans. Currently available treatment options for chronic neuropathic pain are very limited and fraught with dependency concerns. To address this unmet clinical need, we have developed a novel method for capturing plasma-derived SC exosomes (SCDEs) from rodents that regulate key cellular mechanisms in pain processing. These SCDEs recapitulate some of the bioactivity observed in exosomes collected in medium from cultured primary SCs. The major goal of this research project is to determine whether we can exploit the activity of SCDEs to improve pain outcomes following peripheral nerve injury. To accomplish our goals, three Specific Aims are proposed. In Specific Aim 1, we will determine whether a continuum of neuropathic SCDEs or naïve SCDEs regulate neuronal sprouting and calcium signaling in DRG neurons. We will apply advance technologies including single cell RNA transcriptome profiling so that we can define the response of specific neuronal subpopulations in the DRG to SCDEs. Central to this Aim is our discovery that neuropathic, but not naïve, SCDEs are capable of inducing robust neurite outgrowth that may contribute to maintenance of chronic pain states. We hypothesize that by targeting these SCDEs we will identify key mechanisms for improving pain outcomes following peripheral nerve injury therapeutically. In Specific Aim 2, our goal is to discover novel SCDE cargo, and specifically noncoding microRNAs, that are expressed in neuropathic paradigms. This discovery-based Aim establishes a microRNA (miR) signature in SCDEs that may be associated with pain producing and pain alleviating properties. Using NanoString™ technology to measure miRs in SCDEs, we identified a pain alleviating miR-142-3p in naïve SCDEs. The proposed work should identify the SC source (unmyelinated, myelinated, activated or repair phenotype) in nerves that contributes to SCDEs. In Specific Aim 3, we will assess whether SCDE phenotypes regulate neuropathic pain in vivo. This Aim is based on our exciting preliminary data demonstrating that naïve SCDEs delivered systemically inhibit thermal hyperalgesia after partial nerve ligation. SCDEs have intrinsic features, such as the stability, biocompatibility and stealth capacity when circulating in the blood stream. Studies using miR mimics and inhibitors are planned to discover mechanisms conferred by SCDEs to DRG neurons. We consider this project highly innovative because we target SCs and sensory neurons for treating chronic pain.

越来越明显的是，周围神经系统（PNS）中的雪旺细胞（SC）作为一个单位发挥功能， 神经元来调节感觉功能。当PNS在创伤中受损时，SC被激活进行修复。这 涉及到巨大的表型转化如果这一过程异常或受到抑制， 导致慢性衰弱性疼痛，这是在一般人群中观察到的问题，包括许多退伍军人。 目前可用于慢性神经性疼痛的治疗选择非常有限，并且充满依赖性 性问题为了解决这一未满足的临床需求，我们开发了一种新的方法，用于捕获血浆来源的 来自啮齿动物的SC外泌体（SCDE），调节疼痛处理中的关键细胞机制。这些SCDE 概括了在从培养的原代SC的培养基中收集的外来体中观察到的一些生物活性。的 本研究项目的主要目标是确定我们是否可以利用SCDE的活性来改善疼痛 周围神经损伤后的结果。为了实现我们的目标，我们提出了三个具体目标。在 具体目标1，我们将确定是否连续的神经病性SCDE或幼稚SCDE调节神经元 发芽和钙信号在DRG神经元。我们将应用包括单细胞RNA在内的先进技术 转录组分析，以便我们可以定义DRG中特定神经元亚群对 SCDE。这一目标的核心是我们发现神经性但非幼稚性SCDE能够诱导 可能有助于维持慢性疼痛状态的强大神经突生长。我们假设 针对这些SCDE，我们将确定改善周围神经损伤后疼痛结局的关键机制， 治疗上的伤害。在特定目标2中，我们的目标是发现新的SCDE货物，特别是非编码货物， microRNA，在神经病理性范例中表达。这种基于发现的Aim建立了一种microRNA， (miR)可能与疼痛产生和疼痛缓解特性相关的SCDE特征。使用 通过NanoString™技术测量SCDE中的miR，我们在未接受过治疗的患者中鉴定了缓解疼痛的miR-142- 3 p。 SCDE。拟议的工作应确定SC来源（无髓鞘、有髓鞘、激活或修复 表型）的神经，有助于SCDE。在具体目标3中，我们将评估SCDE表型 调节体内神经性疼痛。这个目标是基于我们令人兴奋的初步数据，表明天真的 全身递送的SCDE抑制部分神经结扎后的热痛觉过敏。SCDE具有内在的 这些特性包括稳定性、生物相容性和在血流中循环时的隐形能力。研究 计划使用miR模拟物和抑制剂来发现SCDE赋予DRG神经元的机制。我们 我们认为这个项目非常具有创新性，因为我们针对SC和感觉神经元来治疗慢性疼痛。