Injured axons in the mature central nervous system (CNS), including the optic nerve, cannot regenerate spontaneously. This inability to regenerate causes permanent disability after CNS injuries. A better understanding of the impediments to axon regeneration, and novel approaches towards overcoming them, are necessary for the development of new drugs and procedures that may improve the fate of patients with nervous system injury in the future. Our goal is to enable CNS axon regeneration by elevating intrinsic growth signaling. The RAF kinase is known to drive fast axon growth in embryonic sensory neurons;we therefore will now activate this kinase in the retina.
Our first aim i s to promote regeneration in the injured optic nerve using a conditional B-RAF gain-of-function mouse model. We will then test the roles of signaling molecules downstream of RAF signaling - the MEKs, ERKs and RNDs - for their contributions to B-RAF-driven retinal axon regeneration (Aim 2). Next, we plan to combine activation of B-RAF with activation of PI3-kinase signaling (using a knock-out of the PI3-kinase antagonist PTEN) to see whether this combination will further boost regenerative optic nerve axon growth in vivo (Aim 3). If we can observe regeneration into any of the optic tract nuclei, we will test the mice for any recovery of visual function;such functional recovery being the ultimate goal of all axon regeneration studies. The proposed study will define the roles of RAF signaling and its downstream effectors in the context of optic nerve regeneration, laying groundwork for translational research and for the identification of novel drug targets.

Public Health Relevance

The inability of injured mature axons to regenerate is a major obstacle preventing recovery from traumatic CNS injuries. Axonal damage and regeneration failure in optic nerve are salient features of trauma, glaucoma and other CNS injuries. The proposed study is relevant to public health because it aims to identify a novel and comprehensive means to promote long- distance axon growth and functional recovery following optic nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022409-01
Application #
8275081
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Chin, Hemin R
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$452,500
Indirect Cost
$202,500
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
Zhong, Jian (2016) RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction. Biol Chem 397:215-22
Mathew, Grinu; Hannan, Abdul; Hertzler-Schaefer, Kristina et al. (2016) Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A 113:13156-13161
Karuppagounder, Saravanan S; Alim, Ishraq; Khim, Soah J et al. (2016) Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. Sci Transl Med 8:328ra29
Zhong, Jian (2015) RAFting the rapids of axon regeneration signaling. Neural Regen Res 10:341-3
Huang, Siyi; O'Donovan, Kevin J; Turner, Eric E et al. (2015) Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation. Elife 4:e10874
Latremoliere, Alban; Latini, Alexandra; Andrews, Nick et al. (2015) Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron 86:1393-406
Zhong, Jian; Zou, Hongyan (2014) BMP signaling in axon regeneration. Curr Opin Neurobiol 27:127-34
O'Donovan, Kevin J; O'Keeffe, Catherine; Zhong, Jian (2014) Whole-mount imaging of mouse embryo sensory axon projections. J Vis Exp :
O'Donovan, Kevin J; Ma, Kaijie; Guo, Hengchang et al. (2014) B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. J Exp Med 211:801-14
Zhao, Zhong-Qiu; Huo, Fu-Quan; Jeffry, Joseph et al. (2013) Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest 123:4769-80

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