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Principal Investigator: Fuzheng Guo
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $494,091
Funding agency: National Institute of Neurological Disorders and Stroke
The curious case of PARP1 in CNS myelin formation and repair
Current anti-inflammatory drugs diminish immune attacks yet are ineffective in preventing neurological
progression of multiple sclerosis (MS), the most common demyelinating disorder of the central nervous system
(CNS) with no cure affecting ~ 400,000 people in the USA. Remyelination failure, primarily resulted from
impaired differentiation of oligodendrocytes from oligodendrocyte progenitor cells (i.e. impaired OPC
differentiation), is one of the major causes for MS neurological progression. Remyelination-promoting therapy
represents a promising option in combination with current immunosuppressive medications, for treating MS.
However, few medications are available for targeting myelin repair. Our long-term goal is to discover
remyelination-promoting strategies for treating demyelinating disorders. The objective of this proposal is to
address if and how poly(ADP-ribose) polymerase 1 (PARP1) regulates OPC differentiation and myelination
and determine therapeutic values of PARP1-mediated pathways in myelin repair. PARP1 is a multi-faceted
nuclear protein that has been extensively scrutinized in cancer biology. Upon activation, PARP1 catalyzes the
covalent addition of poly(ADP-ribose) units to its target proteins, a process called PARylation which can be
reversed by the enzyme poly(ADP-ribose) glycohydrolase (PARG). The clinical rationale underlying this
proposal is that oligodendroglial lineage cells in the active but not chronic MS lesions display elevated PARP1
activity, suggesting that PARP1 may be a potential target for remyelination-promoting therapy. However, our
current knowledge of PARP1 in oligodendroglial biology and pathology is extremely limited and its therapeutic
value in remyelination has yet to be determined. The central hypothesis is that PARP1, acting through its
enzymatic activity, is an intrinsic dual-model driver of OPC differentiation and myelination which could be
harnessed to promote myelin repair. Our central hypothesis is built on the conceptual and methodological
foundations laid by our preliminary data of genetic and pharmacological manipulations in vitro and in vivo. The
hypothesis will be test in three specific aims: 1) determine the effect of PARP1 depletion on OPC differentiation
and myelination; 2) define the mechanisms underlying PARP1-regulated OPC differentiation and myelination;
and 3) determine the effects of loss- and gain-of-function of PARP1-mediated PARylation on myelin repair. We
will pursue these three aims by employing unique transgenic models generated in our laboratory. The
proposed research is significant because it will interrogate the therapeutic potential of PARP1 in myelin repair
and lay the conceptual groundwork to develop remyelination-promoting strategies. The expected outcomes will
have an important positive impact because they will establish the first conceptual picture regarding the function
and mechanism of PARP1 in CNS myelin formation and repair and they will provide new data justifying
intervening PARP1-mediated PARylation as a promising option for remyelination-promoting therapy.
Terms: <Ablation><Address><Adenosine 5'-(trihydrogen diphosphate), P'-5-ester with D-ribose, homopolymer><Affect><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Area><Arrowhead><Biology><Brain><Brain Nervous System><CNS Nervous System><Cancer Biology><Cell Body><Cell Communication and Signaling><Cell Death><Cell Lineage><Cell Nucleus><Cell Signaling><Cells><Central Nervous System><Clinical><Curiosities><DNA Damage Repair><DNA Repair><Data><Demyelinating Diseases><Demyelinating Disorders><Demyelinations><Detection><Disseminated Sclerosis><Drugs><Encephalon><Enzyme Gene><Enzymes><Failure><Family><Family member><Foundations><Gene Expression><Genetic><Genome Stability><Genomic Stability><Glycohydrolases><Glycosidases><Glycoside Hydrolases><Goals><Histones><Immune><Immunes><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Impairment><In Vitro><Inflammation><Intracellular Communication and Signaling><Knowledge><Laboratories><Lesion><MS Lesions><Malignant Cell><Mediating><Medication><Medulla Spinalis><Methodology><Mission><Modality><Modeling><Molecular><Molecular Target><Multiple Sclerosis><Multiple Sclerosis Lesions><Myelin><NIH><National Institutes of Health><Neuraxis><Neurologic><Neurological><Nuclear Protein><Nucleus><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Outcome><PARP Polymerase><PARP protein><PARS><Pathology><Pathway interactions><Persons><Pharmaceutical Preparations><Phenocopy><Play><Poly Adenosine Diphosphate Ribose><Poly(ADP-ribose) Polymerases><Poly(ADPribose) Polymerase><Poly-ADPR><Polymerase><Process><Progenitor Cells><Proteins><Public Health><Research><Role><Sagittaria><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Cord><Testing><Therapeutic><Transgenic Model><United States National Institutes of Health><Unscheduled DNA Synthesis><biological signal transduction><cancer cell><central nervous system demyelinating disease><central nervous system demyelinating disorder><de-myelinating diseases><de-myelinating disorders><demyelinate><demyelinating conditions><demyelination diseases><demyelination disorders><drug/agent><gain of function><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><immune suppressive agent><immune suppressor><immunosuppressive substance><immunosuppressor><in vivo><inhibitor><insight><insular sclerosis><loss of function><member><model of animal><myelination><necrocytosis><novel><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><pathway><pharmacologic><poly (ADP-ribose)><poly ADP polymerase><poly ADP ribose synthetase><pre-clinical><preclinical><prevent><preventing><progenitor cell differentiation><progenitor differentiation><re-myelinate><re-myelination><remyelinate><remyelination><repair><repaired><social role><stem and progenitor differentiation><stem cell differentiation><stem cells><transgenic trait>