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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Chin, Hemin R
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University of Rochester
Schools of Dentistry
United States
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Syc-Mazurek, Stephanie B; Rausch, Rebecca L; Fernandes, Kimberly A et al. (2018) Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell Death Dis 9:1095
Harder, Jeffrey M; Williams, Pete A; Soto, Ileana et al. (2018) Jnk2 deficiency increases the rate of glaucomatous neurodegeneration in ocular hypertensive DBA/2J mice. Cell Death Dis 9:705
Fahrenthold, Berkeley K; Fernandes, Kimberly A; Libby, Richard T (2018) Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death. Sci Rep 8:4641
Fernandes, Kimberly A; Mitchell, Katherine L; Patel, Amit et al. (2018) Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Exp Eye Res 171:54-61
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
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
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; Wilson, Michael P et al. (2017) Together JUN and DDIT3 (CHOP) control retinal ganglion cell death after axonal injury. Mol Neurodegener 12:71
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

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