In multiple sclerosis (MS) lesions, remyelination typically fails with recurring or chronic myelin damage. Our preliminary studies show the advantages of a reproducible model of chronic cuprizone demyelination for focusing on this compromised repair response. Importantly, our preliminary data in FGF2-I- mice demonstrates that it is possible to overcome chronic lesion effects on endogenous oligodendrocyte lineage cells to increase remyelination. The FGF2-I- mice do not develop corpus callosum atrophy with chronic demyelination, which indicates a potential for remyelination to attenuate axon damage. Examining the compromised repair after chronic demyelination in wild type mice and the improved response in FGF2-I- mice may reveal potential strategies to enhance recovery in chronic demyelinating diseases. We have shown that the predominant cellular response affected by removal of endogenous FGF2 in vivo during development and remyelination is inhibition of OP differentiation (Murtie et al., 2005a, b). Our current hypothesis is that in chronically demyelinated lesions, inhibitors of OPdifferentiation impair remyelination and prolong pathological reactions in denuded axons. The proposed Aims each address a critical issue to unravel the cellular and molecular interactions mediating OP differentiation effects on remyelination and axon integrity after chronic demyelination.
Aim 1 will characterize the structural effects of FGF2 absence on myelin and axon pathology. Specifically, these studies will correlate myelination status with axonal reactions, as identified by atrophy, neurofilament dephosphorylation, and sodium channel diffusion beyond nodal boundaries. The FGF2 effect on recovery from chonic remyelination can be better exploited to therapeutic advantage in the future once the partners (i.e. target cell type and FGF receptor type) in this response are identified in the studies of Aim 2.
Aim 3 will test whether improved recovery from chronic demyelination is a generalizable effect from removing inhibition of OP differentiation or, alternatively, is an effect specific to the FGF2 pathway. These studies should test the role of inhibitors of OP differentiation in promoting remyelination and preventing axon damage. Furthermore, specific components of the relevant signaling pathways will be identified. These findings can then direct repair strategies that may be a valuable complement to strategies that abrogate myelin damage in MS and other demyelinating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039293-10
Application #
7748964
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Utz, Ursula
Project Start
1999-12-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
10
Fiscal Year
2010
Total Cost
$291,561
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
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Zhou, Yong-Xing; Pannu, Ravinder; Le, Tuan Q et al. (2012) Fibroblast growth factor 1 (FGFR1) modulation regulates repair capacity of oligodendrocyte progenitor cells following chronic demyelination. Neurobiol Dis 45:196-205
Dobson, Nicole R; Moore, Ryan T; Tobin, Jennifer E et al. (2012) Leukemia/lymphoma-related factor regulates oligodendrocyte lineage cell differentiation in developing white matter. Glia 60:1378-90
Hibbits, Norah; Yoshino, Jun; Le, Tuan Q et al. (2012) Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination. ASN Neuro 4:393-408
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Hibbits, Norah; Pannu, Ravinder; John Wu, T et al. (2009) Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination. ASN Neuro 1:
Frost, Emma E; Zhou, Zhicheng; Krasnesky, Kimberley et al. (2009) Initiation of oligodendrocyte progenitor cell migration by a PDGF-A activated extracellular regulated kinase (ERK) signaling pathway. Neurochem Res 34:169-81
Gallo, Vittorio; Armstrong, Regina C (2008) Myelin repair strategies: a cellular view. Curr Opin Neurol 21:278-83
Dobson, Nicole R; Zhou, Yong-Xing; Flint, Nicole C et al. (2008) Musashi1 RNA-binding protein regulates oligodendrocyte lineage cell differentiation and survival. Glia 56:318-30

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