Abstract

In lesions of white matter in Multiple Sclerosis (MS), remyelination occurs to a limited extent, but the disease progresses and remyelination fails, at least in part, due to a shortage of oligodendrocyte (OL) progenitors (13). Therefore, therapies that would stimulate the proliferation and differentiation of OLs would be of tremendous benefit for patients afflicted with MS or other demyelinating diseases. The rationale behind the experiments in this proposal is based on the fact that significant numbers of slowly dividing OL precursors remain in the adult brain of both rodents and humans, and some of these cells mature into oligodendrocytes. Amplifying their numbers would produce a reservoir of immature cells that could re-populate and re-myelinate the denuded axons that are produced in demyelinating diseases such as MS. Furthermore, recent in vitro evidence suggests that differentiated oligodendrocytes can be induced to de-differentiate and proliferate (6). Numerous growth and trophic factors have been identified that promote the proliferation, differentiation or survival of OLs and their progenitors. Therefore, the long-term goal of this research program is to identify novel combinations of cytokines and growth factors that can be developed into therapeutic treatments for patients with demyelinating diseases. The immediate goal of this project is to test the hypothesis that combinatorial administration of CNTF and FGF-2 will induce production of OLs in the adult. To test our central hypothesis, we will pursue five specific aims to demonstrate that: 1) CNTF/FGF-2 enhances proliferation of OL progenitors, 2) CNTF enhances FGF-2 induced proliferation of differentiated OLs, 3) stimulation of the IGF-type I receptor is required for CNTF/FGF-2 mediated mitogenicity, 4) CNTF induces expression of receptors for FGF-2 and IGF-I on OLs or OL progenitors both in vitro and in vivo, and 5) co-administration of CNTF and FGF-2 in vivo will induce OL production in normal and demyelinated adult white matter and will promote remyelination of a focal demyelinating lesion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037560-03
Application #
6330548
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Behar, Toby
Project Start
1998-12-20
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$172,328
Indirect Cost

  Institution

Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033

  Publications

Min, Jungsoo; Singh, Sukhwinder; Fitzgerald-Bocarsly, Patricia et al. (2012) Insulin-like growth factor I regulates G2/M progression through mammalian target of rapamycin signaling in oligodendrocyte progenitors. Glia 60:1684-95
Tyler, William A; Jain, Mohit Raja; Cifelli, Stacey E et al. (2011) Proteomic identification of novel targets regulated by the mammalian target of rapamycin pathway during oligodendrocyte differentiation. Glia 59:1754-69
Tyler, William A; Gangoli, Nitish; Gokina, Pradeepa et al. (2009) Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci 29:6367-78
Romanelli, Robert J; Wood, Teresa L (2008) Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses. J Neurochem 105:2055-68
Wood, Teresa L; Loladze, Vaho; Altieri, Stefanie et al. (2007) Delayed IGF-1 administration rescues oligodendrocyte progenitors from glutamate-induced cell death and hypoxic-ischemic brain damage. Dev Neurosci 29:302-10
Romanelli, Robert J; LeBeau, Andrew P; Fulmer, Clifton G et al. (2007) Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt. J Biol Chem 282:22513-24
Frederick, Terra J; Min, Jungsoo; Altieri, Stefanie C et al. (2007) Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways. Glia 55:1011-22
Ness, Jennifer K; Scaduto Jr, Russell C; Wood, Teresa L (2004) IGF-I prevents glutamate-mediated bax translocation and cytochrome C release in O4+ oligodendrocyte progenitors. Glia 46:183-94
Frederick, Terra J; Wood, Teresa L (2004) IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E-cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells. Mol Cell Neurosci 25:480-92
Ness, Jennifer K; Wood, Teresa L (2002) Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis. Mol Cell Neurosci 20:476-88

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