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.

总结 周围神经损伤，无论是创伤，手术并发症，或神经病变的结果，折磨数百万人 仅在美国就有1000万人患有糖尿病，是全世界残疾和痛苦的主要原因。的 周围神经损伤的症状包括麻木、刺痛、肌肉无力、疼痛和步态障碍。 尽管迫切需要，但目前还没有批准的治疗方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集中在 外周神经本身，特别是神经元和雪旺细胞，我们采取了一种新的方法， 重点是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 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。 虽然目前还没有用于治疗人类疾病，但巨噬细胞也可以用来治疗选择性疾病。 疾病，由于血神经屏障的破坏，周围神经损伤是一个潜在的目标， 巨噬细胞在周围神经再生中的既定作用。在研究表明 代谢对巨噬细胞功能的重要性，我们 正在研究一个国家的变化 关键的代谢转运蛋白，单羧酸转运蛋白1（MCT 1），对巨噬细胞的功能。我们 最近发表的一篇论文显示，在巨噬细胞中选择性下调MCT 1， 吞噬作用，减少促再生细胞因子的产生，并损害外周神经的恢复 损伤更重要的是，从临床的角度来看，我们还发现， 巨噬细胞加速外周神经再生，并且巨噬细胞静脉内注射到 老鼠瞄准受伤的神经并参与修复。根据这些结果，我们目前的建议将 研究了两种加速小鼠神经损伤恢复的潜在机制。在目标1中，我们 用脂质纳米颗粒离体转化巨噬细胞以上调MCT 1或促再生途径 分别表达MCT 1质粒或包封黄芩苷，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 相同的脂质纳米颗粒能够在直接静脉内给药后在体内转化巨噬细胞 注射，导致周围神经损伤的加速恢复。如果成功的话， 该提案不仅将验证一种新的技术和目标，以加速神经损伤后的恢复， 还潜在地提供了在其它巨噬细胞依赖性病症中操纵巨噬细胞的试剂， 例如不愈合的皮肤伤口、肺或肝纤维化以及肌肉损伤。