Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells (RGCs). While numerous cell signaling pathways have been implicated in glaucomatous RGC death, the molecular cascades that kill RGCs in glaucoma need to be defined. Previously, we have shown that RGCs die by apoptosis in glaucoma and that the molecule BAX, an important regulator of apoptosis, is required for RGC death in a mouse glaucoma model. BAX is a member of the Bcl2 family of proteins, a group of molecules that play a critical role in regulating the survival of many neurons. An important next step in defining the molecular signaling pathways that lead to vision loss in glaucoma is to identify the molecules that activate BAX in RGCs. BAX is known to be regulated by other Bcl2 family members. These family members summate the various signaling pathways active in a cell, determining if a cell lives or dies. The Bcl2 family members that regulate BAX activity can be divided into two groups, pro-survival members and pro-apoptotic (death) members. It is the interplay between these two groups that determines whether BAX is activated and, thus, whether a RGC survives a glaucomatous insult. We hypothesize that both pro-survival and pro-death signaling pathways are active in RGCs during a glaucomatous insult and that these signaling pathways exert their effects through the regulation of Bcl2 family members. Here, we will identify both the pro-death and pro-survival members of the Bcl2 family that regulate BAX activation in glaucoma and we will test the importance of these molecules in glaucoma through genetic manipulation. These experiments will use the DBA/2J mouse glaucoma model, allowing us to apply the powerful tools and resources of mouse genetics to identify the molecular components that regulate RGC survival and death. These experiments will provide information about the complexity of the signaling pathways active in glaucoma and identify genes that may account for the differences in susceptibility to glaucoma observed between people. Furthermore, the results will provide candidate molecules that could be targeted for glaucoma therapies, both ones that could be stimulated to protect RGCs and ones whose activity could be blocked to prevent RGC death.
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 critical 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.
|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|
Showing the most recent 10 out of 25 publications