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 #
5R01EY018606-10
Application #
9398122
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Liberman, Ellen S
Project Start
2008-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Rochester
Department
Ophthalmology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Syc-Mazurek, Stephanie B; Fernandes, Kimberly A; Wilson, Michael P et al. (2017) Together JUN and DDIT3 (CHOP) control retinal ganglion cell death after axonal injury. Mol Neurodegener 12:71
Apara, Akintomide; Galvao, Joana; Wang, Yan et al. (2017) KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS. J Neurosci 37:9632-9644
Harder, Jeffrey M; Braine, Catherine E; Williams, Pete A et al. (2017) Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U S A 114:E3839-E3848
Syc-Mazurek, Stephanie B; Fernandes, Kimberly A; Libby, Richard T (2017) JUN is important for ocular hypertension-induced retinal ganglion cell degeneration. Cell Death Dis 8:e2945
Hedberg-Buenz, Adam; Christopher, Mark A; Lewis, Carly J et al. (2016) Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification. Exp Eye Res 146:370-85
Fernandes, K A; Bloomsburg, S J; Miller, C J et al. (2016) Novel axon projection after stress and degeneration in the Dscam mutant retina. Mol Cell Neurosci 71:1-12
Fernandes, Kimberly A; Harder, Jeffrey M; Williams, Pete A et al. (2015) Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities. Exp Eye Res 141:42-56
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
Mac Nair, Caitlin E; Fernandes, Kimberly A; Schlamp, Cassandra L et al. (2014) Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush. J Neuroinflammation 11:194
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

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