The overall hypothesis of the current work is that oligodendrocytes (OLGs), the myelinating cells of the central nervous system are critically influenced by the well-defined trophic factor, brain-derived neurotrophic factor (BDNF). The effects of BDNF are mediated through trkB and its associated MAP kinase, PI3 kinase-Akt, and PLC-gamma pathways. BDNF supports OLG proliferation and differentiation during brain development and throughout life. Work performed during the initial funding period supports this hypothesis. Using basal forebrain (BF) OLG cultures, we found that BDNF elicits 2-3 fold increases in DNA synthesis and numbers of myelin basic protein + (MBP) cells. Using in vivo studies we found that BDNF knockout animals express 38 percent fewer NG2 oligodendrocyte progenitor cells than wild-type littermates and that BDNF +/_ adult mice exhibit reduced MBP expression. Moreover, coimmunocytochemical analysis revealed that the BDNF receptor, trkB, is expressed on mature APC+ OLGs in adult mice. These observations support the possibility that OLGs are critically regulated by BDNF. To extend these studies we now propose to 1) test in vivo relevance of the culture work and (2) determine signaling mechanisms underlying BDNF actions. In particular, we will: (1) Identify receptors and signaling pathways mediating BDNF effects, (2) Define the in vivo expression pattern of trkB in OLGs and (3) Define the roles of BDNF and BDNF receptors in vivo by using knockout mice. These studies explore the role BDNF may play in the development and maintenance of OLGs in vivo. We suggest that this work may provide significant new insights into deficits in myelination that occur in devastating neural diseases characterized by the loss of oligodendrocytes and an inability to repopulate the lesioned area. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036647-04A2
Application #
6694994
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (02))
Program Officer
Utz, Ursula
Project Start
1998-06-01
Project End
2007-06-30
Budget Start
2003-07-15
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$258,519
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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