White Matter Restoration in Vascular Cognitive Impairment and dementia

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: GUODONG  CAO
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $561,842
Funding agency: National Institute of Neurological Disorders and Stroke

Abstract
Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia after Alzheimer’s disease.
Although the causes for VCID are not clear, increasing evidence suggests cerebral hypoperfusion is the dominant pathogenic
process. Cerebral hypoperfusion causes the death of oligodendrocytes, the only myelin (the key component in nerve fiber)
producing cells in CNS, leading to white matter injury (WMI) which is closely related to VCID. Thus, interventions targeted
at WMI—an area that remains poorly understood—may provide a new therapy for both WMI and VCID. We have
successfully reprogrammed reactive astrocytes into oligodendrocyte progenitor cells (iOPCs) by three transcription factors
(named SOA) in ischemic brain. Reprogrammed OPCs can proliferate/differentiate into mature oligodendrocytes, repair
WMI and improve sensorimotor and cognitive function. Thus, we intend to test the therapeutic potential of reprogrammed
oligodendrocytes in WM restoration and in cognitive dysfunction/memory loss in mouse models that mimic common carotid
artery (CCA) hypoperfusion caused by arteriosclerotic CCA stenosis. The central hypothesis is that in situ
reprogramming of activated astrocytes into oligodendrocytes can restore white matter integrity and improve long-
term cognitive recovery in VCID models induced by CCA hypoperfusion. The following three Aims are proposed:
Aim 1 will characterize the maturity of reprogrammed OPCs and their role in WM restoration in CCA hypoperfusion models
in both genders and the underlaying mechanism whether reprogrammed OPCs enhance WM restoration by enhancing axonal
remyelination and stimulating axonal sprouting. Aim 2 will test if iOPCs enhance long-term sensorimotor and cognitive
function as well as axonal function in the needle CCA hypoperfusion model in young and aged mice. Aim 3 will test if ICV
administration of recombinant SOA pool protein can reprogram reactive astrocytes into oligodendrocytes, restore WM
integrity, and improve cognitive recovery in a needle CCA hypoperfusion model. The proposed study is the first to
reprogram astrocytes in situ into viable oligodendrocytes and will provide a novel therapeutic approach for WMI and VCID
as well other CNS diseases that involve WMI.

Terms: <AD dementia><Action Potentials><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amentia><Area><Astrocytes><Astrocytus><Astroglia><Axon><Axonal Transport><Axoplasmic Transport><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Brain><Brain Ischemia><Brain Nervous System><CNS Diseases><CNS Injury><CNS disorder><Carotid Artery Narrowing><Carotid Artery Stenosis><Carotid Stenosis><Cause of Death><Cell Body><Cell Reprogramming><Cell Survival><Cell Viability><Cells><Central Nervous System Diseases><Central Nervous System Disorders><Cessation of life><Chronic><Cicatrix><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Common carotid artery><DWI (diffusion weighted imaging)><DWI-MRI><Death><Dementia><Demyelinations><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disturbance in cognition><Dysfunction><Electron Microscopy><Electrophysiology><Electrophysiology (science)><Encephalon><Ensure><Environment><Female><Fiber><Functional disorder><Gender><General Transcription Factor Gene><General Transcription Factors><Gliosis><Goals><Guidelines><Image><Impaired cognition><In Situ><In Vitro><Infarction><Infusion><Infusion procedures><Injury><Intervention><Intervention Strategies><Ischemia><Ischemic Encephalopathy><Lentiviral Vector><Lentivirus Vector><Link><Long-Term Potentiation><Longterm Potentiation><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measurement><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory Loss><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Myelin><NMR Imaging><NMR Tomography><Names><Natural regeneration><Needles><Nerve Fibers><Neurophysiology / Electrophysiology><Nuclear Magnetic Resonance Imaging><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Outcome Assessment><Pathogenicity><Physiopathology><Primary Senile Degenerative Dementia><Process><Progenitor Cells><Proliferating><Proteins><Recombinants><Recovery><Recovery of Function><Regeneration><Replacement Therapy><Role><Scars><Sensorimotor functions><Structure><Techniques><Testing><Transcription Factor Proto-Oncogene><Transcription factor genes><Zeugmatography><aged mice><aged mouse><astrocytic glia><axon damage><axon injury><axonal damage><axonal injury><axonal sprouting><behavior test><behavioral test><brain tissue><cardiac disease induced cognitive impairment><cellular reprogramming><central nervous system injury><cerebral hypoperfusion><cognitive dysfunction><cognitive enhancement><cognitive function><cognitive loss><cognitive recovery><dMRI><demyelinate><diffusion tensor imaging><elderly mice><electrophysiological><experiment><experimental research><experimental study><experiments><functional recovery><hypoperfusion><imaging><immunogenicity><improved><in vivo><infarct><infusions><injured CNS><injuries><injury and repair><innovate><innovation><innovative><insight><interventional strategy><male><memory decline><mouse model><murine model><myelination><name><named><naming><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><old mice><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><overexpress><overexpression><pathophysiology><primary degenerative dementia><progenitor cell differentiation><progenitor differentiation><programs><re-myelinate><re-myelination><regenerate><remyelinate><remyelination><repair><repaired><restoration><senile dementia of the Alzheimer type><social role><stem and progenitor differentiation><stem cell differentiation><stem cells><substantia alba><therapeutic evaluation><therapeutic testing><transcription factor><translational opportunities><translational potential><vascular cognitive impairment and dementia><vascular contributions to cognition/dementia><vascular contributions to cognitive impairment and dementia><white matter><white matter injury>