Developing macrophage-based therapies for peripheral nerve injuries

开发基于巨噬细胞的周围神经损伤疗法

• 批准号: 10740955
• 负责人: BRETT M. MORRISON
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740955
• 关键词: Abbreviations; Acceleration; Adoptive Cell Transfers; Area; Autoimmune Diseases; Autopsy; Blood flow; Blood-Nerve Barrier; Bone Marrow; Central Nervous System; Clinical; Control Groups; Crush Injury; Data; Disease; Down-Regulation; Encapsulated; Functional disorder; Gait; Immune; Immune checkpoint inhibitor; Immune system; Immunotherapy; Impairment; Inflammatory; Infusion procedures; Injections; Injury; Intravenous; Investigation; Laboratories; Liver Fibrosis; Lymphocyte Transfusion; Macrophage; Malignant Neoplasms; Medicine; Metabolic; Metabolism; Modification; Monoclonal Antibodies; Mus; Muscle; Muscle Weakness; Myelin; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Neurons; Neuropathy; Numbness; Pain; Paper; Peripheral Nerves; Peripheral nerve injury; Persons; Phagocytosis; Phenotype; Plasmids; Play; Production; Publishing; Pulmonary Fibrosis; Recovery; Regenerative pathway; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Schwann Cells; Secondary to; Specificity; Surgical complication; Symptoms; Tail; Techniques; Testing; Time; Transgenic Mice; Trauma; United States; Up-Regulation; Veins; Wild Type Mouse; Work; axon regeneration; axonal degeneration; cell type; cohort; cytokine; disability; experimental study; functional improvement; human disease; in vivo; injury recovery; intravenous injection; lipid nanoparticle; monocyte; nerve injury; nerve repair; novel; novel strategies; peripheral nerve regeneration; pre-clinical; regeneration following injury; regenerative; repaired; sciatic nerve; skin wound; tool; wound healing

Summary Peripheral nerve injuries, whether the result of trauma, surgical complications, or neuropathies, afflict millions of people in the United States alone and are a major cause of disability and suffering throughout the world. The symptoms of peripheral nerve injury include numbness, tingling, muscle weakness, pain, and gait dysfunction. Despite the critical need, there are currently no approved therapies to accelerate peripheral nerve regeneration following injury. Though many researchers are focusing their investigations of nerve injury on components of the peripheral nerve itself, particularly neurons and Schwann cells, we have taken a novel approach and are focusing on components of the immune system-- specifically macrophages. Immunotherapy, or the manipulation of the immune system to treat human diseases, is a rapidly growing area in medicine that has shown great promise, particularly in treating autoimmune diseases and cancer. Immunotherapies can take many forms, including monoclonal antibodies, checkpoint inhibitors, and regulatory T lymphocyte transfusions. Though not currently used for treating human diseases, macrophages could also be harnessed to treat select diseases, with peripheral nerve injuries being a potential target due to disruption of the blood-nerve barrier and the established role of macrophages in peripheral nerve regeneration. Building on research demonstrating the importance of metabolism for the function of macrophages, we are studying the impact of alterations in a critical metabolic transporter, monocarboxylate transporter 1 (MCT1), on the function of macrophages. We recently published a paper showing that downregulation of MCT1 selectively in macrophages impairs phagocytosis, reduces production of pro-regenerative cytokines, and impairs recovery from peripheral nerve injury. More importantly from a clinical perspective, we also found that upregulation of MCT1 selectively in macrophages accelerates peripheral nerve regeneration and that macrophages injected intravenously into mice target the injured nerve and participate in repair. Based on these results, our current proposal will investigate two potential mechanisms for accelerating nerve recovery from injury in mice. In Aim 1, we will transform macrophages ex vivo to upregulate MCT1 or pro-regenerative pathways with lipid nanoparticles expressing MCT1 plasmid or encapsulating baicalin, respectively, and test whether adoptive cell transfer of these transformed macrophages accelerates nerve repair and recovery. In Aim 2, we will test whether these same lipid nanoparticles are capable of transforming macrophages in vivo following direct intravenous injections, resulting in accelerated recovery from peripheral nerve injuries. If successful, the experiments in this proposal will not only validate a novel technique and target for accelerating nerve recovery following injury, but also potentially provide an agent for manipulating macrophages in other macrophage-dependent conditions, such as non-healing skin wounds, pulmonary or liver fibrosis, and muscle injuries.

概括 周围神经损伤，无论是外伤、手术并发症还是神经病变造成的，都困扰着数百万人 仅在美国，这一疾病就成为全世界残疾和痛苦的主要原因。这 周围神经损伤的症状包括麻木、刺痛、肌肉无力、疼痛和步态功能障碍。 尽管需求迫切，但目前尚无批准的疗法来加速周围神经再生 受伤后。尽管许多研究人员将神经损伤的研究重点放在了 对于周围神经本身，特别是神经元和施万细胞，我们采取了一种新颖的方法， 重点关注免疫系统的组成部分——特别是巨噬细胞。免疫疗法，或 操纵免疫系统来治疗人类疾病是医学中一个快速发展的领域， 显示出巨大的前景，特别是在治疗自身免疫性疾病和癌症方面。免疫疗法可以采取 有多种形式，包括单克隆抗体、检查点抑制剂和调节性 T 淋巴细胞输注。 虽然巨噬细胞目前尚未用于治疗人类疾病，但也可用于治疗特定疾病 疾病，由于血神经屏障的破坏，周围神经损伤成为潜在的目标 巨噬细胞在周围神经再生中的既定作用。以研究为基础 新陈代谢对于巨噬细胞功能的重要性，我们 正在研究改变的影响 关键代谢转运蛋白，单羧酸转运蛋白 1 (MCT1)，对巨噬细胞功能的影响。我们 最近发表的一篇论文表明，MCT1 在巨噬细胞中选择性下调会损害 吞噬作用，减少促再生细胞因子的产生，并损害周围神经的恢复 受伤。更重要的是，从临床角度来看，我们还发现MCT1选择性上调 巨噬细胞加速周围神经再生，静脉注射巨噬细胞 小鼠瞄准受伤的神经并参与修复。根据这些结果，我们当前的提案将 研究加速小鼠神经损伤恢复的两种潜在机制。在目标 1 中，我们将 使用脂质纳米颗粒离体转化巨噬细胞以上调 MCT1 或促再生途径 分别表达MCT1质粒或封装黄芩苷，并测试是否过继细胞转移 这些转化的巨噬细胞加速神经修复和恢复。在目标 2 中，我们将测试这些是否 相同的脂质纳米颗粒能够在直接静脉注射后在体内转化巨噬细胞 注射，从而加速周围神经损伤的恢复。如果成功的话，本次实验 该提案不仅将验证一种加速损伤后神经恢复的新技术和目标，而且 还可能提供一种在其他巨噬细胞依赖性条件下操纵巨噬细胞的试剂， 例如无法愈合的皮肤伤口、肺或肝纤维化以及肌肉损伤。