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Principal Investigator: Jackson Mace
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Nearly three million people worldwide are currently living with multiple sclerosis (MS), a complex neurological disease
that primarily affects individuals between 20-45 years of age. MS is characterized by peripheral immune cell infiltration
into the central nervous system (CNS) with associated reactive gliosis, oligodendrocyte (OL) death, demyelination, and
neuroaxonal degeneration. Some of the infiltrates that migrate to the CNS are lymphocytes that target the myelin sheaths of
axons. Existing therapies predominately inhibit adaptive immune cells in circulation; however, these medications are often
not effective in halting the pathophysiology that underlies progressive CNS degeneration in MS, where immune cell
infiltration and activation are minimal. No therapies currently exist to treat this pathology because the molecular
mechanisms by which CNS lesions occur in patients with MS is not fully understood. Since disability in progressive MS is
driven by the chronic loss of OLs and neurons, this study will investigate the distinct degenerative process of both cell types
utilizing relevant models. The ultimate objective of this proposed research is to identify how neurons and OLs die in the
context of MS. Understanding this will help identify therapeutic targets to stop these degenerative processes from occurring
in patients with MS. For the past decade, our lab has studied a novel, non-apoptotic cell death pathway, parthanatos, that
plays an active role in various neurological conditions. Parthanatos-inducing conditions that lead to DNA damage, such as
high ROS concentrations, are pathologically prevalent across many neurological diseases including MS. Herein, our lab has
created a mouse line with a point mutation that selectively ablates the enzymatic activity of the downstream executioner of
parthanatos cell death, macrophage migration inhibitory factor (MIF) nuclease, and synthesized a compound that
specifically inhibits MIF nuclease. Both genetic and pharmacologic developments have been shown to mediate protection
of dopaminergic neurons in the alpha-synuclein plaque-forming fibril model of Parkinson’s Disease. These experimental
tools will be used here to assess the therapeutic efficacy of targeting MIF nuclease in the experimental autoimmune
encephalomyelitis (EAE) mouse model of MS and neonatal-derived mouse OLs following exposure to MS-relevant insults.
My preliminary data suggest that genetic ablation of MIF nuclease in EAE mice led to decreased neurologic impairment
over time. Importantly, genetic ablation of MIF nuclease in EAE mice did not affect peak EAE disease severity or peripheral
immune cell infiltration into the spinal cord. I also determined that genetic ablation and pharmacologic inhibition of MIF
nuclease in EAE mice protected against retinal ganglion cell and lumbar spinal cord neuron loss. I further revealed that OL
precursor cells underwent parthanatos following DNA damage, and that this cell death process was limited by inhibiting
upstream parthanatos enzymes in vitro. Therefore, I hypothesize that neurons and OLs die by parthanatos in MS, and
that inhibition of MIF nuclease will protect against neuron and OL degeneration in MS-relevant models. Collectively,
if neurons and OLs degenerate by parthanatos in MS as indicated by my preliminary data, this proposed research could
establish a pharmacological target that can be inhibited to directly mitigate the ongoing loss of grey and white matter in the
CNS of patients with this disease.
Terms: <Ablation><Acute><Adenosine 5'-(trihydrogen diphosphate), P'-5-ester with D-ribose, homopolymer><Affect><Age Years><Atrophic><Atrophy><Autoimmune Diseases><Autopsy><Axon><Biologic Models><Biological Models><Blood Plasma><Blood Serum><Body Tissues><Brain><Brain Nervous System><CNS Nervous System><CNS degeneration><Caspase><Caspase Gene><Cell Body><Cell Death><Cell Death Process><Cell-Death Protease><Cells><Central Nervous System><Cessation of life><Chronic><Chronic Disease><Chronic Illness><Circulation><Clinical><Complex><Cranial Nerve II><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><DA Neuron><DNA Damage><DNA Injury><Data><Death><Degenerative Disorder><Demyelinating Diseases><Demyelinating Disorders><Demyelinations><Development><Disabling><Disease><Disorder><Disseminated Sclerosis><Dopamine neuron><Drugs><Dysfunction><EAE><Encephalon><Enzyme Gene><Enzymes><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Exposure to><Functional disorder><Genetic><Gliosis><Granzyme><ICE-like protease><Immune><Immune infiltrates><Immune system><Immunes><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Impairment><In Vitro><Individual><Infiltration><Inflammation><Inflammatory><Inflammatory Infiltrate><Lesion><Lumbar Portion of Spinal Cord><Lumbar Spinal Cord><Lumbar spinal cord structure><Lymphatic cell><Lymphocyte><Lymphocytic><MS Lesions><MS patient><Macrophage Migration Inhibition Factors><Macrophage Migration Inhibitory Factor><Mediating><Medication><Medulla Spinalis><Mice><Mice Mammals><Migration Inhibition Factor><Migration Inhibitory Factor><Model System><Modeling><Molecular><Multiple Sclerosis><Multiple Sclerosis Lesions><Murine><Mus><Myelin><Myelin Sheath><NAC precursor><Neonatal><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neuraxis><Neurocyte><Neurologic><Neurologic Disorders><Neurologic Dysfunctions><Neurological><Neurological Disorders><Neuron Degeneration><Neurons><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Optic Nerve><Oral><PARK1 protein><PARK4 protein><PARP Inhibitor><PARP Polymerase><PARP protein><PARP-1 inhibitor><PARPi><PARS><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathology><Pathway interactions><Patients><Peripheral><Persons><Pharmaceutical Preparations><Phase><Physiopathology><Plasma><Plasma Serum><Play><Point Mutation><Poly Adenosine Diphosphate Ribose><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) Polymerases><Poly(ADP-ribose) polymerase 1 inhibitor><Poly(ADPribose) Polymerase><Poly-ADPR><Primary Parkinsonism><Process><Relapsing-Remitting Multiple Sclerosis><Research><Reticuloendothelial System, Serum, Plasma><Retina><Retinal Ganglion Cells><Role><SNCA><SNCA protein><Second Cranial Nerve><Serum><Severity of illness><Single-Nucleus Sequencing><Spinal Cord><Symptoms><Testing><Therapeutic><Time><Tissues><Treatment Efficacy><United States><Variant><Variation><Veins><Wild Type Mouse><Work><a-syn><a-synuclein><adult youth><alpha synuclein><alpha synuclein gene><alphaSP22><arylpyruvate keto-enol tautomerase><asyn><autoimmune condition><autoimmune disorder><autoimmune encephalomyelitis><autoimmunity disease><axon damage><axon injury><axonal damage><axonal injury><cell type><central nervous system degeneration><chronic disorder><cohort><cystein protease><cystein proteinase><cysteine endopeptidase><cytokine><de-myelinating diseases><de-myelinating disorders><degenerative condition><degenerative disease><demyelinate><demyelinating conditions><demyelination diseases><demyelination disorders><design><designing><develop therapy><developmental><differential expression><differentially expressed><disability><disease severity><dopaminergic neuron><drug/agent><experiment><experimental research><experimental study><experiments><glial activation><glial cell activation><gray matter><immune cell infiltrate><immune suppressive agent><immune suppressor><immunosuppressive substance><immunosuppressor><in vivo><inhibitor><innovate><innovation><innovative><insight><insular sclerosis><intervention development><intervention efficacy><lymph cell><migration><mouse model><multiple sclerosis patient><murine model><necrocytosis><necropsy><neonatal exposure><neonatal mice><nerve cell death><nerve cell loss><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neurological disease><neurological dysfunction><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuroprotection><neuroprotective><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclease><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><p-hydroxyphenylpyruvate tautomerase><pathophysiology><pathway><patients with MS><patients with multiple sclerosis><people with Multiple sclerosis><pharmacologic><phenylpyruvate tautomerase><poly (ADP-ribose)><poly ADP polymerase><poly ADP ribose synthetase><postmortem><precursor cell><prevent><preventing><programs><retinal ganglion><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><substantia alba><substantia grisea><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic candidate><therapeutic efficacy><therapeutic target><therapy development><therapy efficacy><tool><trafficking><transcriptional differences><transcriptomics><treatment development><white matter><wildtype mouse><young adult><young adulthood><α synuclein gene><α-syn><α-synuclein>