We propose to investigate why mature, central nervous system (CMS) neurons fail to regenerate after injury, and how this failure depends on the developmental control of gene expression. Mature retinal ganglion cells (RGCs) fail to regenerate after their axons are severed, yet axons in the embryonic CMS can regenerate after injury. The loss of this embryonic regenerative ability correlates with the loss of RGCs1 intrinsic ability to rapidly extend axons. Interestingly, neonatal RGCs do not decrease their axon growth ability by an intrinsic aging mechanism, but rather they are signaled to do so by amacrine cells. In this proposal we will investigate the cellular and molecular mechanism for this loss of intrinsic axon growth ability. We demonstrate that the amacrine-signaled decrease in RGC axon growth ability correlates with an increased ability to elongate dendrites, and is dependent on new gene expression in RGCs. In the first aim we will use an in vivo model in which amacrine cells largely fail to develop to ask whether amacrine cells are required for the developmental loss of intrinsic axon growth ability by RGCs. In the second aim we will characterize the amacrine cell membrane-associated cue that is sufficient to signal embyronic RGCs to decrease their axon growth ability, and use microarrays to develop a list of candidates genes. In the third aim we will use powerful transfection and RNAi techniques to investigate the molecular basis of RGCs1 decreased axon and increased dendrite growth abilities. Our goal is to revert mature, postnatal RGCs to their embryonic axon growth ability, and to enhance RGC regeneration after optic nerve injury in vivo. Our ultimate goal is to develop new treatments to promote RGC regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis and optic neuropathies, and to extend our understanding to more broadly promote CMS regeneration, for example after spinal cord injury or in neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061348-04
Application #
7846178
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Kleitman, Naomi
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$298,206
Indirect Cost
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Kunzevitzky, Noelia J; Willeford, Kevin T; Feuer, William J et al. (2013) Amacrine cell subtypes differ in their intrinsic neurite growth capacity. Invest Ophthalmol Vis Sci 54:7603-13
Chang, Elma E; Goldberg, Jeffrey L (2012) Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 119:979-86
Santos, Andrea Rachelle C; Corredor, Raul G; Obeso, Betty Albo et al. (2012) ?1 integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival. PLoS One 7:e48332
Corredor, Raul G; Trakhtenberg, Ephraim F; Pita-Thomas, Wolfgang et al. (2012) Soluble adenylyl cyclase activity is necessary for retinal ganglion cell survival and axon growth. J Neurosci 32:7734-44
Jo, Sungro; Kalló, Imre; Bardóczi, Zsuzsanna et al. (2012) Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism. J Neurosci 32:8491-500
Steketee, Michael B; Moysidis, Stavros N; Jin, Xiao-Lu et al. (2011) Nanoparticle-mediated signaling endosome localization regulates growth cone motility and neurite growth. Proc Natl Acad Sci U S A 108:19042-7
Kunzevitzky, Noelia J; Almeida, Monica V; Duan, Yuanli et al. (2011) Foxn4 is required for retinal ganglion cell distal axon patterning. Mol Cell Neurosci 46:731-41
Trakhtenberg, Ephraim F; Goldberg, Jeffrey L (2011) Immunology. Neuroimmune communication. Science 334:47-8
Moore, Darcie L; Apara, Akintomide; Goldberg, Jeffrey L (2011) Kruppel-like transcription factors in the nervous system: novel players in neurite outgrowth and axon regeneration. Mol Cell Neurosci 47:233-43
Moore, Darcie L; Goldberg, Jeffrey L (2011) Multiple transcription factor families regulate axon growth and regeneration. Dev Neurobiol 71:1186-211

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