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

基本信息

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
项目类别：
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

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

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项目摘要

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.

概括外周神经损伤，无论是创伤，外科并发症还是神经病的结果，都折磨着数百万仅在美国，在全世界造成残疾和苦难的主要原因。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。尽管需要至关重要，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调查集中在周围神经本身，尤其是神经元和雪旺细胞，我们采取了一种新颖的方法，并且是专注于免疫系统的组件 - 特别是巨噬细胞。免疫疗法或操纵免疫系统以治疗人类疾病，是医学中迅速增长的领域在治疗自身免疫性疾病和癌症方面表现出了巨大的希望。可以接受免疫疗法许多形式，包括单克隆抗体，检查点抑制剂和调节性T淋巴细胞输注。尽管目前尚未用于治疗人类疾病，但也可以利用巨噬细胞来治疗选择疾病，外周神经损伤是由于血液障碍和巨噬细胞在周围神经再生中的既定作用。在研究的基础上证明代谢对于巨噬细胞功能的重要性，我们正在研究改变关键代谢转运蛋白，单羧酸盐转运蛋白1（MCT1），涉及巨噬细胞的功能。我们最近发表的论文表明，巨噬细胞中MCT1的下调损害吞噬作用，降低促增再生成细胞因子的产生，并损害外周神经的恢复受伤。从临床角度来看，更重要的是，我们还发现MCT1有选择地上调巨噬细胞加速了周围神经再生，巨噬细胞静脉注射到小鼠针对受伤的神经并参与维修。基于这些结果，我们当前的建议将研究了两种潜在的机制，以加速小鼠损伤的神经恢复。在AIM 1中，我们将将巨噬细胞转化为实体，以脂质纳米颗粒上调MCT1或促进途径分别表达MCT1质粒或封装Baicalin，并测试是否的收养细胞转移这些转化的巨噬细胞加速了神经修复和恢复。在AIM 2中，我们将测试是否相同的脂质纳米颗粒能够在直接静脉内转化体内巨噬细胞注射，导致外周神经损伤加速恢复。如果成功，则实验建议不仅会验证一种新技术和目标，以加速受伤后神经恢复，而且还可以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药物，例如非愈合皮肤伤口，肺或肝纤维化以及肌肉损伤。