The lack of nerve regeneration following spinal cord injury has been attributed to several factors, all of which must be overcome for functional recovery to occur. The presence of outgrowth inhibitory cues in the central nervous system, but not the peripheral nervous system, contribute to the inability of the central nervous system to regenerate. One well established obstacle in spinal cord regeneration is the expression of myelin inhibitory proteins at the site of injury. Myelin inhibitory proteins cause the nerve to collapse and retract away from the injury site, thus preventing regeneration. This work will focus on elucidating the mechanisms by which myelin inhibitory proteins prevent axon regeneration in the central nervous system. Myelin inhibitory proteins act through the Nogo receptor (NgR), which is expressed on the surface of growing axons and signals through its interaction with the p75 neurotrophin receptor (p75). The mechanisms by which NgR and p75 inhibit axon outgrowth have not been fully established. One known mechanism by which p75 inhibits axon outgrowth is through a signaling cascade involving the Rho family of GTPases. p75 lacks intrinsic catalytic activity and relies on intracellular adaptor proteins to signal, such as TNF Receptor Associated Factor 6 (TRAF6). Preliminary data from our laboratory suggests a role for TRAF6 in the inhibition of axon outgrowth by myelin inhibitory proteins. We hypothesize that TRAF6 is required for the transduction of the growth inhibitory signal downstream of the NgR-p75 complex.
The specific aims of our research are to 1) Determine whether TRAF6 is required for axon outgrowth inhibition by myelin proteins 2) Evaluate whether TRAF6 is recruited by p75 following binding of the myelin inhibitory proteins to regulate GTPase activity 3) Investigate the mechanism by which TRAF6 is involved in inhibition of axon outgrowth. Axon outgrowth will be studied in neurons lacking TRAF6 both in vitro and in vivo to establish a role for TRAF6 downstream of myelin inhibitory proteins. Using primary neuron cultures, we will assess the role of TRAF6 in the regulation of GTPase activity. Data from our laboratory indicates a possible functional interaction between TRAF6 and p21-activated kinase, a known modulator of the actin cytoskeleton. We will pursue this interaction as a mechanism by which TRAF6 inhibits axonal growth. This work will provide valuable insight into the biochemical processes involved in the inhibition of nerve regeneration. This knowledge will allow us to develop therapeutic strategies to promote neuronal growth following spinal cord injury and thus prevent paralysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS061403-02
Application #
7565926
Study Section
Special Emphasis Panel (ZNS1-SRB-M (51))
Program Officer
Kleitman, Naomi
Project Start
2008-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$25,739
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Wei, Chunyao; Thatcher, Elizabeth J; Olena, Abigail F et al. (2013) miR-153 regulates SNAP-25, synaptic transmission, and neuronal development. PLoS One 8:e57080
Perdigoto, Ana Luisa; Chaudhry, Nagarathnamma; Barnes, Gregory N et al. (2011) A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons. Mol Cell Neurosci 46:235-44