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Principal Investigator: Thomas E Lane
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $846,461
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract: An important unmet clinical need for patients with the demyelinating disease multiple sclerosis (MS)
is an effective method for promoting remyelination that can ameliorate clinical symptoms associated with
demyelination and restore motor function while limiting immune cell infiltration into the CNS. The long-term
objectives of this research proposal are to i) define how chemokine signaling controls neuroinflammation and
disease progression, ii) assess the effects of chemokine signaling in regulating oligodendrocyte progenitor cell
(OPC) maturation and remyelination, iii) further characterize how engrafted human and mouse neural
progenitor cells enhance axonal integrity, promote remyelination and influence
neuroinflammation/demyelination, iv) define mechanisms by which microglia restrict the severity of
demyelination and influence remyelination. To accomplish these goals, we will use a well-accepted pre-clinical
animal models of MS. For over 20 years, my laboratory has used intracranial infection of susceptible C57BL/6
mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) as a model of viral-induced
demyelination to study molecular and cellular events controlling neurioinflammation, demyelination, and
remyelination. Proposed experimental procedures that will aid in accomplishing our research goals will include
genetic approaches through generation of mice in which targeted genes are either selectively induced/ablated
to assess effect on disease progression and repair, CRISPR technology to ablate specific target genes in NPC
cultures, single cell and nuclear RNA sequencing on immune cells and resident CNS cells and use of 2-photon
(2P) microscopy to visualize axonal damage/repair and remyelination. Collectively, we believe our
experimental goals outlined in this proposal will provide new insight into the pathogenesis of MS as well as
identify new targets for therapeutic intervention to impede disease progression and promote remyelination.
Terms: <2-photon microscopy><Ablation><Animal Model><Animal Models and Related Studies><Area><Axon><C57BL/6 Mouse><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Culture Techniques><Cell Interaction><Cell Maturation><Cell Signaling><Cell-to-Cell Interaction><Cells><Chemotactic Cytokines><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Demyelinating Diseases><Demyelinating Disorders><Demyelinations><Disease><Disease Progression><Disorder><Disseminated Sclerosis><Engraftment><Event><Functional RNA><Generations><Genes><Goals><Homologous Chemotactic Cytokines><Hortega cell><Human><Immune><Immune infiltrates><Immunes><Infection><Intercrines><Intracellular Communication and Signaling><JHM strain><Laboratories><MHV-JHM><MS patient><Mediating><Methods><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular><Motor><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Multiple Sclerosis><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><Neural Stem Cell><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nuclear RNA><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Patients><Predisposition><Procedures><RNA Seq><RNA sequencing><RNAseq><Research><Research Proposals><SIS cytokines><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><Therapeutic Intervention><Untranslated RNA><Viral><Visualization><associated symptom><axon damage><axon injury><axonal damage><axonal injury><biological signal transduction><cell culture><cell cultures><chemoattractant cytokine><chemokine><co-morbid symptom><co-occuring symptom><comorbid symptom><concurrent symptom><cooccuring symptom><de-myelinating diseases><de-myelinating disorders><demyelinate><demyelinating conditions><demyelination diseases><demyelination disorders><genetic approach><genetic strategy><gitter cell><immune cell infiltrate><improved><insight><insular sclerosis><intervention therapy><mesoglia><microglial cell><microgliocyte><model of animal><mouse hepatitis virus JHM><multiple sclerosis patient><murine hepatitis coronavirus><nerve stem cell><neural inflammation><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuroinflammation><neuroinflammatory><neuron progenitors><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><noncoding><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><patients with MS><patients with multiple sclerosis><people with Multiple sclerosis><perivascular glial cell><pre-clinical><preclinical><re-myelinate><re-myelination><remyelinate><remyelination><repair><repaired><surgery><symptom association><symptom comorbidity><transcriptome sequencing><transcriptomic sequencing><two photon excitation microscopy><two photon microscopy><viral-induced demyelination><virus-induced demyelination>