Under normal circumstances, mature retinal ganglion cells (RGCs) cannot regenerate their axons after optic nerve damage and soon begin to die. However, it was shown in the prior grant period that if macrophages become activated in the eye, many RGCs survive axotomy and regenerate their axons through the inhibitory environment of the optic nerve. A protein from macrophages was identified that may mediate these effects.
Aim 1 will investigate whether this macrophage-derived protein is sufficient to stimulate optic nerve regeneration in vivo, determine whether this protein is normally present in the developing visual system, and identify its receptor.
Aim 2 will test the hypothesis that the macrophage-derived protein and certain ancillary factors induce distinct molecular changes required for axon regeneration, and investigate the functional significance of some of the gene products that are induced. This work will capitalize on studies done in the prior grant period which used fluorescence-activated cell sorting to purify RGCs, followed by microarray analysis, to investigate the program of gene expression associated with successful axon regeneration.
Aim 3 will test the hypothesis that a purine-sensitive kinase that was isolated in the prior funding period is part of a signal transduction pathway linking growth factor stimulation to the changes in gene expression required for axon regeneration. This research will add significantly to our understanding of optic nerve regeneration, and may provide novel targets for therapeutic interventions in glaucoma and other degenerative or traumatic disorders of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005690-26
Application #
6915201
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (14))
Program Officer
Oberdorfer, Michael
Project Start
1990-08-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
26
Fiscal Year
2005
Total Cost
$364,500
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Omura, Takao; Omura, Kumiko; Tedeschi, Andrea et al. (2015) Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron 86:1215-27
Kurimoto, Takuji; Yin, Yuqin; Habboub, Ghaith et al. (2013) Neutrophils express oncomodulin and promote optic nerve regeneration. J Neurosci 33:14816-24
Roh, Miin; Zhang, Yan; Murakami, Yusuke et al. (2012) Etanercept, a widely used inhibitor of tumor necrosis factor-? (TNF-?), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS One 7:e40065
de Lima, Silmara; Koriyama, Yoshiki; Kurimoto, Takuji et al. (2012) Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc Natl Acad Sci U S A 109:9149-54
Benowitz, Larry I; Popovich, Phillip G (2011) Inflammation and axon regeneration. Curr Opin Neurol 24:577-83
Kurimoto, Takuji; Yin, Yuqin; Omura, Kumiko et al. (2010) Long-distance axon regeneration in the mature optic nerve: contributions of oncomodulin, cAMP, and pten gene deletion. J Neurosci 30:15654-63
Benowitz, Larry I; Yin, Yuqin (2010) Optic nerve regeneration. Arch Ophthalmol 128:1059-64
Yin, Yuqin; Cui, Qi; Gilbert, Hui-Ya et al. (2009) Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A 106:19587-92
Lorber, Barbara; Howe, Mariko L; Benowitz, Larry I et al. (2009) Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nat Neurosci 12:1407-14
Cui, Q; Yin, Y; Benowitz, L I (2009) The role of macrophages in optic nerve regeneration. Neuroscience 158:1039-48

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