Disability in clinical neurology frequently results from axonal damage rather than neuronal cell loss. Spinal cord injury is an example where successful axonal regeneration holds the potential for extensive functional recovery. Recent work has uncovered a number of the molecular determinants of axonal regeneration. The CMS myelin proteins, Nogo-A, MAG and OMgp, inhibit axonal growth in tissue culture. All three proteins bind to one axonal receptor, the Nogo-66 receptor (NgR), to initiate a signaling cascade that inhibits axonal extension. Reactive astrocytes secrete chondroitin sulfate proteoglycans (CSPGs) that also limit axonal growth, especially near injury sites. The growth of adult axons is dependent on cell autonomous positive factors as well as the presence of extracellular inhibitory proteins. Peripheral axotomy successfully induces a regeneration gene program, while central axotomy of the same neuron has much less effect. Proteins that are induced selectively after peripheral axotomy but not central axotomy include GAP-43, SPRRIA and Fn14. This project seeks to examine the role of myelin inhibitors and CSPGs in CMS axonal regeneration using genetic and molecular means, with spinal cord injury as a model. The role of SPRR1A and Fn14 in peripheral nerve regeneration will also be assessed genetically, and their mechanism of axon growth enhancement will be probed. Together, these aims seek to advance our molecular understanding of the extrinsic and intrinsic factors that determine the success of axonal regeneration, and have the potential to provide new therapeutic modalities to improve nervous system function after a wide range of chronic neurologic injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039962-07
Application #
7017088
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Kleitman, Naomi
Project Start
2000-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
7
Fiscal Year
2006
Total Cost
$369,209
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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Akbik, Feras; Cafferty, William B J; Strittmatter, Stephen M (2012) Myelin associated inhibitors: a link between injury-induced and experience-dependent plasticity. Exp Neurol 235:43-52
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
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
Gimbel, David A; Nygaard, Haakon B; Coffey, Erin E et al. (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367-74

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