Many nervous system injuries sever distal axons, but leave proximal neuronal cell bodies intact. Recovery of function is largely dependent on the degree of axonal regeneration. After CNS damage, as occurs in spinal cord injury, axonal regeneration is routinely dismal. Nogo was recently identified as a CNS myelin-derived inhibitor of axonal regeneration. An understanding of the mechanism of Nogo action is critical to assessing and modulating its physiologic role. Here, we seek to characterize a Nogo receptor and to define its physiologic role. In preliminary studies, we have characterized a high affinity Nogo-66 binding site and obtained functional evidence that a novel brain-specific leucine-rich repeat protein mediates Nogo action. In the first specific aim, we will characterize this receptor protein by determining structure-function relationships for Nogo binding and axon repulsion, and by analyzing expression patterns before and after neural trauma. The absence of an intracellular signaling domain in this receptor protein implies an interaction with a second transmembrane receptor subunit responsible for transduction.
The second aim i s to identify this additional receptor subunit through its affinity for the identified Nogo binding receptor protein and by analyzing Nogo-induced tyrosine phosphorylation. Thirdly, a strain of mice lacking the Nogo receptor protein will be generated by homologous recombination. Neuronal development and the degree of anatomical recovery after neuronal trauma in these mice will be characterized. The identification of Nogo and its receptor provides the opportunity for novel and rational therapeutic interventions in spinal cord injury. This research may also prove applicable to a wide range of chronic brain axonal injuries, such as traumatic brain injury, white matter strokes and chronic progressive multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042304-03
Application #
6639819
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (01))
Program Officer
Kleitman, Naomi
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$367,875
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Shim, Sang-Ohk; Cafferty, William B J; Schmidt, Eric C et al. (2012) PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Mol Cell Neurosci 50:193-200
Wang, Xingxing; Duffy, Philip; McGee, Aaron W et al. (2011) Recovery from chronic spinal cord contusion after Nogo receptor intervention. Ann Neurol 70:805-21
Huebner, Eric A; Kim, Byung G; Duffy, Philip J et al. (2011) A multi-domain fragment of Nogo-A protein is a potent inhibitor of cortical axon regeneration via Nogo receptor 1. J Biol Chem 286:18026-36
Matsushita, Haruka; Endo, Shota; Kobayashi, Eiji et al. (2011) Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells. J Biol Chem 286:25739-47
Zai, Laila; Ferrari, Christina; Dice, Carlie et al. (2011) Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. J Neurosci 31:5977-88
Cafferty, William B J; Duffy, Philip; Huebner, Eric et al. (2010) MAG and OMgp synergize with Nogo-A to restrict axonal growth and neurological recovery after spinal cord trauma. J Neurosci 30:6825-37
Hånell, Anders; Clausen, Fredrik; Björk, Maria et al. (2010) Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice. J Neurotrauma 27:1297-309
Harel, Noam Y; Song, Kang-Ho; Tang, Xin et al. (2010) Nogo receptor deletion and multimodal exercise improve distinct aspects of recovery in cervical spinal cord injury. J Neurotrauma 27:2055-66
Gunther, Erik C; Strittmatter, Stephen M (2010) Beta-amyloid oligomers and cellular prion protein in Alzheimer's disease. J Mol Med (Berl) 88:331-8

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