Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells (RGCs). Axonal injury is an important, early insult to RGCs in glaucoma and axonal damage precedes cell body degeneration. Identifying the local axonal signaling pathways that initiate these changes is an important step in understanding glaucoma and other axonopathies. Following axonal injury, phosphorylation-dependent signal relay events are among the first changes to occur and these signals likely trigger fate-determining events in the axon and cell body. The mitogen-activated protein kinase (MAPK) family plays an integral role in signal transduction in response to changes in the cellular environment by integrating diverse signals arising from cellular stressors and initiating changes in gene expression. c-Jun N-terminal kinases, (JNK1-3) are MAPK family members that are known to be involved in axonal injury signaling. JNK activation is known to occur in human glaucoma patients and has been documented in various glaucoma models. We have shown that the JNKs are activated in RGC axons soon after injury and those they are important mediators of axonal injury-induced RGC death. Furthermore, we have shown that RGC death is dependent on activation of the canonical JNK substrate, the transcription factor JUN. In this application we propose a series of experiments designed to define a key axonal injury pathway-JNK signaling-in glaucomatous neurodegeneration and to test our central hypothesis: A JNK signaling pathway is a critical mediator of RGC death after axonal injury and is the signaling pathway that links axonal injury to RGC death. Specifically, we will determine: 1) the JNK dependent events that control RGC death after a glaucomatous injury;2) whether activation of the transcription factor JUN is required for glaucomatous RGC death;and 3) the identity of the axonal injury-induced kinases that control JNK activation and axon degeneration in glaucoma. Since axonal injury and degeneration are likely to be key events in glaucoma and JNK signaling is active in glaucomatous eyes, understanding this pathway will be important for understanding the pathophysiology of glaucoma. The experiments outlined in this application will: define new molecules fundamental in the axonal injury and degeneration cascade, identify molecular events that are early in the injury signaling cascade which are ideal targets for therapeutic intervention and define the critical pathological insults that trigger axonal injury and degeneration in glaucoma.

Public Health Relevance

Vision loss in glaucoma is caused by the death of the output neurons in the retina, the retinal ganglion cells. This application is focused on identifying critial molecules that kill retinal ganglion cells in glaucoma. These data will identify potential pharmaceutical targets for the treatment and prevention of glaucoma as well as genes that may underlie patient susceptibility to vision loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY018606-06A1
Application #
8630588
Study Section
Special Emphasis Panel (BVS)
Program Officer
Chin, Hemin R
Project Start
2008-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
University of Rochester
Department
Ophthalmology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Huang, Liang; Hu, Fang; Xie, Xiaoling et al. (2014) Pou4f1 and pou4f2 are dispensable for the long-term survival of adult retinal ganglion cells in mice. PLoS One 9:e94173
Fernandes, Kimberly A; Harder, Jeffrey M; John, Simon W et al. (2014) DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury. Neurobiol Dis 69:108-16
Soto, Ileana; Howell, Gareth R; John, Cai W et al. (2014) DBA/2J mice are susceptible to diabetic nephropathy and diabetic exacerbation of IOP elevation. PLoS One 9:e107291
Fernandes, Kimberly A; Harder, Jeffrey M; Kim, Jessica et al. (2013) JUN regulates early transcriptional responses to axonal injury in retinal ganglion cells. Exp Eye Res 112:106-17
Howell, Gareth R; Soto, Ileana; Libby, Richard T et al. (2013) Intrinsic axonal degeneration pathways are critical for glaucomatous damage. Exp Neurol 246:54-61
Harder, J M; Libby, R T (2013) Deficiency in Bim, Bid and Bbc3 (Puma) do not prevent axonal injury induced death. Cell Death Differ 20:182
Noel, Jennifer M; Fernandez de Castro, Juan P; Demarco Jr, Paul J et al. (2012) Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage. Exp Eye Res 97:137-47
Fernandes, Kimberly A; Harder, Jeffrey M; Fornarola, Laura B et al. (2012) JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death. Neurobiol Dis 46:393-401
Howell, Gareth R; Soto, Ileana; Zhu, Xianjun et al. (2012) Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest 122:1246-61
Howell, Gareth R; Walton, David O; King, Benjamin L et al. (2011) Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data. BMC Genomics 12:429

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