Document text
Principal Investigator: BRETT M. MORRISON
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2023
Award: $450,313
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Abbreviations><Acceleration><Adoptive Cell Transfers><Area><Autoimmune Diseases><Autopsy><Blood flow><Blood monocyte><Blood-Nerve Barrier><Bone Marrow><Bone Marrow Reticuloendothelial System><CNS Nervous System><Cancers><Central Nervous System><Checkpoint inhibitor><Clinical><Clinical Treatment Moab><Control Groups><Crush Injury><Data><Disease><Disorder><Down-Regulation><Dysfunction><Encapsulated><Functional disorder><Gait><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunes><Immunologically Directed Therapy><Immunotherapy><Impairment><Inflammatory><Infusion><Infusion procedures><Injections><Injury><Intermediary Metabolism><Intravenous><Investigation><Investigators><Laboratories><Liver Fibrosis><Loss of Sensation><Lung Tissue Fibrosis><Lymphocyte Transfusion><Macrophage><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Medicine><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modification><Monoclonal Antibodies><Murine><Mus><Muscle><Muscle Tissue><Muscle Weakness><Muscular Weakness><Myelin><Mφ><Natural regeneration><Nerve><Nerve Cells><Nerve Crush><Nerve Regeneration><Nerve Unit><Neural Cell><Neuraxis><Neurilemma Cell><Neurilemmal Cell><Neuro-regeneration><Neurocyte><Neurons><Neuropathy><Neuroregeneration><Numbness><Pain><Painful><Paper><Peripheral Nerves><Peripheral nerve injury><Persons><Phagocytosis><Phenotype><Physiopathology><Plasmids><Play><Production><Publishing><Pulmonary Fibrosis><Recovery><Regeneration><Regenerative pathway><Regulatory T-Lymphocyte><Research><Research Personnel><Researchers><Role><Schwann Cells><Secondary to><Specificity><Surgical complication><Symptoms><Tail><Techniques><Testing><Time><Transgenic Mice><Trauma><Treg><United States><Up-Regulation><Upregulation><Veins><Wild Type Mouse><Work><Wound Repair><adoptive cell therapy><adoptive cellular therapy><autoimmune condition><autoimmune disorder><autoimmunity disease><axon degeneration><axon regeneration><axonal degeneration><axonal regeneration><cell type><cohort><cutaneous wound><cytokine><degenerative axon><dermal wound><disability><experiment><experimental research><experimental study><experiments><fibrosis in the lung><fibrotic liver><functional improvement><hepatic fibrosis><human disease><immune check point inhibitor><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improve function><improved functional outcomes><in vivo><infusions><injuries><injury recovery><intravenous injection><lipid based nanoparticle><lipid nanoparticle><lung fibrosis><mAbs><malignancy><monoclonal Abs><monocyte><muscular><necropsy><neoplasm/cancer><nerve injury><nerve reconstruction><nerve repair><nervous system regeneration><neural injury><neural regeneration><neuronal><neuropathic><neuroregenerative><new approaches><novel><novel approaches><novel strategies><novel strategy><pathophysiology><peripheral nerve crush injuries><peripheral nerve regeneration><postmortem><pre-clinical><preclinical><recovery after injury><recovery following injury><recovery post injury><regenerate><regenerated nerve><regeneration following injury><regeneration pathway><regenerative><regulatory T-cells><repair><repaired><sciatic nerve><skin wound><social role><surgery complication><tool><wildtype mouse><wound healing><wound resolution>