Regulation of Schwann Cell Mitochondria Homeostasis in Painful Peripheral Neuropathy

疼痛性周围神经病中雪旺细胞线粒体稳态的调节

• 批准号: 10790951
• 负责人: WENDY M. CAMPANA
• 金额: $ 43.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790951
• 关键词: Acute; Address; Afferent Neurons; Anticonvulsants; Axon; Behavior; Bioenergetics; Cell Separation; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cutaneous; Cytoplasm; Data; Demyelinations; Development; Distal; Drug Targeting; Endoneuriums; Etiology; Event; Fiber; Foundations; Genes; Genetic; Goals; Hepatocyte; Heterogeneity; Homeostasis; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Injury; LDL-Receptor Related Protein 1; Ligands; Link; Lipids; Lipoprotein Receptor; Local Anesthetics; Medical; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Morphology; Mus; Myelin; Nerve; Nerve Fibers; Neuroglia; Neurons; Neuropathy; Nociception; Opioid; Paclitaxel; Pain; Pain management; Paresthesia; Pathologic; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phase II Clinical Trials; Phosphotransferases; Physiological; Positioning Attribute; Predisposition; Property; Proteins; Proteome; Proteomics; Quality of life; Receptor Signaling; Regulation; Research; Research Project Grants; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Signaling Protein; Steroids; Stress; Symptoms; Techniques; Testing; Therapeutic; Transgenic Mice; Wild Type Mouse; Work; addiction; blood glucose regulation; chemotherapy; chronic neuropathic pain; clinically significant; curative treatments; human data; improved; in vivo; inflammatory pain; innovation; lipid metabolism; metabolomics; mitochondrial DNA mutation; motor deficit; mtTF1 transcription factor; neuroinflammation; novel; novel strategies; pain reduction; painful neuropathy; prevent; receptor; receptor binding; repair function; repaired; response; sciatic nerve; side effect; spontaneous pain; targeted treatment; transmission process

PROJECT SUMMARY Peripheral neuropathies have heterogeneous etiologies and can emerge from traumatic, metabolic and chemotherapy induced events. Neuropathic pain is a major symptom of peripheral neuropathies, which is characterized by spontaneous pain, burning and paresthesia. Often it is associated with devastating losses of quality of life. Currently, treatments are limited and burden patients with side effects and addiction. Identifying novel strategies for pain treatment addresses a substantial unmet medical need. Research in mechanisms of painful peripheral neuropathy (PPN) has largely focused on sensory neurons, however, peripheral glia, Schwann cells (SCs), emerge as an essential component of the functional unit with sensory neurons that regulate pain states. Yet, mechanisms underlying SC contributions to PPN are largely unknown. Mitochondria dysregulation in neurons has been identified as a mechanism associated with PPN. Although, two studies show that genetic deletion of a key mitochondrial protein elicits a progressive demyelinating neuropathy, there are no studies linking a SC repair receptor signaling pathway (which could be targeted therapeutically) with mitochondria heterogeneities and/or homeostasis in SCs, relevant to neuropathic pain. We identified the low-density lipoprotein receptor related protein (LRP1) as a key SC repair receptor after injury. An important property of LRP1 is its ability to regulate lipid metabolism and glucose homeostasis, and therefore, control cellular bioenergetics. We propose that LRP1 directly regulates mitochondrial dynamics and function in SCs to optimize bioenergetic homeostasis in peripheral nerves. Our prior work investigating SC LRP1 in neuroinflammation and pain, and exciting new preliminary data showing LRP1 regulation of mitochondria numbers in the SC cytoplasm of myelinated fibers, uniquely positions us to test this hypothesis. In Aim 1, we will examine regulation of SC mitochondrial heterogeneities and bioenergetics. We propose analyses in whole nerve lysates and isolated primary SC cultures (mSC) from transgenic mice in which LRP1 is conditionally deleted from SCs (scLRP1-/-). We plan to challenge mSC metabolism with an innovative LRP1 activator, currently in phase II clinical trials. We also will test how LRP1 regulated SC mitochondria respond to stress by treatment with a chemotherapy agent known to induce PPN. In Aim 2, we will identify the mitochondrial proteome by using an unbiased proteomics screen from neuropathic and naive SCs isolated from scLRP1-/- and scLRP1+/+, respectively. We then build on the protein blueprint of how conditional deletion of LRP1 in SCs triggers PPN and apply global untargeted metabolomics to identify key metabolite changes. These studies will reveal entirely new information about mitochondria dynamics, content, and metabolism of SCs related to PPN.

项目概要 周围神经病具有不同的病因，可能由创伤性、代谢性和 化疗引起的事件。神经性疼痛是周围神经病的主要症状， 其特征是自发性疼痛、烧灼感和感觉异常。通常它与毁灭性的损失有关 生活质量。目前，治疗方法有限，并且给患者带来副作用和成瘾的负担。识别 疼痛治疗的新策略解决了巨大的未满足的医疗需求。机制研究 疼痛性周围神经病（PPN）主要集中在感觉神经元，然而，周围神经胶质细胞，施万 细胞（SC）作为具有调节疼痛的感觉神经元的功能单元的重要组成部分出现 州。然而，SC 对 PPN 贡献的机制在很大程度上尚不清楚。线粒体失调 神经元中的这种变化已被确定为与 PPN 相关的机制。尽管有两项研究表明遗传 关键线粒体蛋白的缺失会引发进行性脱髓鞘性神经病，目前尚无研究 将 SC 修复受体信号通路（可作为治疗目标）与线粒体连接起来 SC 的异质性和/或稳态，与神经性疼痛相关。我们确定了低密度 脂蛋白受体相关蛋白（LRP1）作为损伤后 SC 修复的关键受体。的一个重要属性 LRP1 具有调节脂质代谢和葡萄糖稳态的能力，因此可以控制细胞 生物能量学。我们认为 LRP1 直接调节 SC 中的线粒体动力学和功能以优化 周围神经的生物能量稳态。我们之前的工作调查 SC LRP1 在神经炎症和 令人兴奋的新初步数据显示 LRP1 对 SC 细胞质中线粒体数量的调节 有髓纤维，使我们能够检验这一假设。在目标 1 中，我们将审查 SC 的监管 线粒体异质性和生物能学。我们建议对整个神经裂解物和分离的神经裂解物进行分析 来自转基因小鼠的原代 SC 培养物 (mSC)，其中 LRP1 从 SC 中有条件删除 (scLRP1-/-)。 我们计划用创新的 LRP1 激活剂挑战 mSC 代谢，目前正处于 II 期临床试验中。我们 还将测试 LRP1 如何通过化疗药物调节 SC 线粒体对应激的反应 已知可诱发 PPN。在目标 2 中，我们将使用公正的蛋白质组学来鉴定线粒体蛋白质组 分别从 scLRP1-/- 和 scLRP1+/+ 分离的神经病变 SC 和幼稚 SC 中进行筛选。然后我们建立在 SC 中 LRP1 条件性删除如何触发 PPN 并应用全局非靶向的蛋白质蓝图 代谢组学来识别关键代谢物的变化。这些研究将揭示有关的全新信息 与 PPN 相关的 SC 的线粒体动力学、含量和代谢。