Glaucoma is a disease characterized by visual field loss as a result of the death of retinal ganglion cells. Although increased intraocular pressure remains the most clearly defined risk factor for glaucoma, it is becoming clear that a wide range of other factors can also lead to ganglion cell loss. Pharmacological or surgical regulation of intraocular pressure can stabilize many patients but for some there is still a progressive loss of vision. Thus, there is an urgent need to develop new rational strategies to slow or prevent neuronal loss occurring in glaucoma. There is abundant evidence that the eye, like other regions of the CNS, contains endogenous neurotrophic/neuroprotective factors that function to limit cell injury. It is the basic premise of this proposal that these neuroprotective mechanisms can be exploited to prevent much of the cell death associated with diseases such as glaucoma. This proposal focuses on one neuroprotective molecule, CNTF, a factor that has already been shown to have potent neuroprotective effects in a number of CNS regions including the retina and is a leading candidate for slowing the progression of ganglion cell loss. In our preliminary data we present evidence that CNTF supports the survival of purified rat RGCs in low density cultures and that its downstream effector STAT3 prevents RGCs from degenerating in ischemia- reperfusion injury. We now propose a series of experiments to test if RGCs can be prevented from dying in the presence of toxic levels of glutamate by CNTF. In a first aim we will define the pathways used by CNTF to exert its protective action. Second, we will examine whether M?ller glia can respond to CNTF and provide synergistic protection to RGCs by the secretion of additional neuroprotective factors or a range of other responses. Finally we will test whether the protective pathways activated by CNTF lead to a reduction in reactive oxygen species generation by mitochondria through the activation of mitochondrial uncoupling proteins.

Public Health Relevance

Glaucoma is a blinding disease that affects over 65 million people worldwide. There is still not a good understanding of the basic biochemical mechanisms which cause the death of retinal cells and subsequent loss of vision. This research will identify some of these biochemical pathways. The results of this research will lead to the identification of target molecules for which new therapeutic drugs can be designed.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013865-08
Application #
8204925
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Chin, Hemin R
Project Start
2002-02-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$370,613
Indirect Cost
$130,613
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Barnstable, Colin J; Reddy, Rajini; Li, Hong et al. (2016) Mitochondrial Uncoupling Protein 2 (UCP2) Regulates Retinal Ganglion Cell Number and Survival. J Mol Neurosci 58:461-9
Popova, Evgenya Y; Pinzon-Guzman, Carolina; Salzberg, Anna C et al. (2016) LSD1-Mediated Demethylation of H3K4me2 Is Required for the Transition from Late Progenitor to Differentiated Mouse Rod Photoreceptor. Mol Neurobiol 53:4563-81
Pinzon-Guzman, Carolina; Xing, Tiaosi; Zhang, Samuel Shao-Min et al. (2015) Regulation of rod photoreceptor differentiation by STAT3 is controlled by a tyrosine phosphatase. J Mol Neurosci 55:152-9
Li, Weiyi; Yang, Chen; Lu, Jing et al. (2014) Tetrandrine protects mouse retinal ganglion cells from ischemic injury. Drug Des Devel Ther 8:327-39
Popova, Evgenya Y; Barnstable, Colin J; Zhang, Samuel Shao-Min (2014) Cell type-specific epigenetic signatures accompany late stages of mouse retina development. Adv Exp Med Biol 801:3-8
Popova, Evgenya Y; Grigoryev, Sergei A; Fan, Yuhong et al. (2013) Developmentally regulated linker histone H1c promotes heterochromatin condensation and mediates structural integrity of rod photoreceptors in mouse retina. J Biol Chem 288:17895-907
Huang, Ping; Huo, Yanjiao; Lou, Lucy X et al. (2013) CD4 positive T helper cells contribute to retinal ganglion cell death in mouse model of ischemia reperfusion injury. Exp Eye Res 115:131-9
Popova, Evgenya Y; Xu, Xuming; DeWan, Andrew T et al. (2012) Stage and gene specific signatures defined by histones H3K4me2 and H3K27me3 accompany mammalian retina maturation in vivo. PLoS One 7:e46867
Pinzon-Guzman, Carolina; Zhang, Samuel Shao-Min; Barnstable, Colin J (2011) Specific protein kinase C isoforms are required for rod photoreceptor differentiation. J Neurosci 31:18606-17
Pinzon-Guzman, Carolina; Shaomin Zhang, Samuel; Barnstable, Colin J (2010) Protein kinase C regulates rod photoreceptor differentiation through modulation of STAT3 signaling. Adv Exp Med Biol 664:21-8

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