Retinal ganglion cell death is the final common pathway of almost all diseases of the optic nerve including glaucoma. Glaucoma is a leading cause of blindness and, although a number of risk factors have been identified, its causes remain unclear. Excitotoxins may be a major cause of cell death in glaucoma and the overall goal of this project is to determine the molecular mechanisms by which a variety of excitotoxic agents induce ganglion cell apoptosis. The proposal has four specific aims. In the first aim the hypothesis that glutamate induces apoptosis through a caspase-9 mediated pathway will be tested. In addition, other factors, including ischemia will be tested to determine whether they can act synergistically to exacerbate the effects of low concentrations of excitotoxins. In the second specific aim the hypothesis that mitochondrial uncoupling proteins can reduce excitotoxic ganglion cell death will be tested. The sensitivity of ganglion cells to excitotoxic and ischemic insults will be tested in culture and in the intact eye using genetically engineered mouse strains that overexpress or under express the protein UCP2.
The third aim will test the hypothesis that functional disorders of Muller glial cells may contribute to excitotoxic ganglion cell death. In particular, a variety of agents will be tested for their ability to inhibit Muller cell glutamate uptake.
The final aim will test the hypothesis that direct cell contact can protect ganglion cells from the toxic effects of nitric oxide. The specificity of this effect will be tested with a variety of cell types and the need for membrane contact by living cells will be tested using a variety of biochemical fractions. Overall, the experiments in this proposal will shed light on mechanisms of cell death of particular relevance to glaucoma. They will also further elucidate mechanisms of interaction between retinal ganglion cells and Muller glial cells. By identifying molecules that can alter responses to excitotoxins or ischemia, this proposal is likely to provide potential targets for novel therapeutic interventions to prevent or slow the progression of blindness resulting from glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013865-05
Application #
7012189
Study Section
Special Emphasis Panel (ZRG1-SSS-R (02))
Program Officer
Liberman, Ellen S
Project Start
2002-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$359,229
Indirect Cost
Name
Yale University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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
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
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; 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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