Although glaucoma is a leading cause of worldwide blindness, neither the precise pathogenic mechanisms, which lead to retinal ganglion cell death in glaucoma, nor effective strategies for neuroprotection are known. Tumor necrosis factor-alpha (TNF-alpha) has recently been identified to be a mediator of retinal ganglion cell death in glaucoma. In vitro evidence demonstrates that TNF-alpha secreted by activated glial cells in response to glaucomatous stressors, such as elevated intraocular pressure and ischemia, can induce apoptotic death of retinal ganglion cells. Glial production of TNF-alpha is increased, and TNF receptor-1, a death receptor, is upregulated in retinal ganglion cells and their axons in glaucomatous human eyes. There is also compelling in vivo evidence obtained from a rat model of high-pressure glaucoma, which demonstrates the pathogenic role of TNF-a in these eyes. (1) Similar to glaucomatous human eyes, the expression of TNF-alpha and TNF receptor-1 are increased in rat eyes following intraocular pressure elevation; (2) TNF-alpha signaling is involved in cell death in these eyes, as evidenced by the activation of retinal caspase-8 -a proximal effector protein in the TNF receptor family cell death pathway; (3) anti-TNF-alpha treatment in ocular hypertensive rat eyes can provide neuroprotection. Additional in vivo evidence comes from studies using the optic nerve crush injury model in mice deficient for TNF receptor-1. Although this is not a model for glaucoma, findings of these studies provide evidence that TNF-alpha signaling is involved in the death of retinal ganglion cells following optic nerve injury. Thus, current evidence presented in this application collectively provides a strong rationale for further evaluation of the TNF-alpha mediated cell death in glaucoma. The proposed experiments aim to identify the precise mechanisms of TNF-alpha-mediated cell death and neuroprotection in retinal ganglion cells and glial cells, using in vitro and in vivo models. Using primary co-cultures, activation of caspases and mitochondrial events, and activation of native protection mechanisms and selected kinase pathways will be separately studied in retinal ganglion cells and glial cells exposed to exogenous TNF-alpha. Using a rat glaucoma model, the relationship between the induction of endogenous TNF-alpha and cell death will be studied, in vivo. In addition, the effectiveness of a specific anti-TNF-alpha treatment to provide neuroprotection will be further determined in this in vivo model using both the functional and the anatomical outcomes. An improved understanding of the precise mechanisms of cell death and protection in studies proposed in this application should facilitate efforts to effectively manipulate the survival of retinal ganglion cells in glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013813-03
Application #
6904436
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Liberman, Ellen S
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$257,250
Indirect Cost
Name
University of Louisville
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Tezel, Gülgün (2014) A decade of proteomics studies of glaucomatous neurodegeneration. Proteomics Clin Appl 8:154-67
Krizaj, David; Ryskamp, Daniel A; Tian, Ning et al. (2014) From mechanosensitivity to inflammatory responses: new players in the pathology of glaucoma. Curr Eye Res 39:105-19
Tezel, Gulgun (2013) Immune regulation toward immunomodulation for neuroprotection in glaucoma. Curr Opin Pharmacol 13:23-31
Tezel, Gulgun (2013) A proteomics view of the molecular mechanisms and biomarkers of glaucomatous neurodegeneration. Prog Retin Eye Res 35:18-43
Tezel, Gulgun; Yang, Xiangjun; Luo, Cheng et al. (2012) An astrocyte-specific proteomic approach to inflammatory responses in experimental rat glaucoma. Invest Ophthalmol Vis Sci 53:4220-33
Tezel, Gulgun; Thornton, Ivey L; Tong, Melissa G et al. (2012) Immunoproteomic analysis of potential serum biomarker candidates in human glaucoma. Invest Ophthalmol Vis Sci 53:8222-31
Tezel, Gulgun (2011) The immune response in glaucoma: a perspective on the roles of oxidative stress. Exp Eye Res 93:178-86
Yang, Xiangjun; Luo, Cheng; Cai, Jian et al. (2011) Neurodegenerative and inflammatory pathway components linked to TNF-α/TNFR1 signaling in the glaucomatous human retina. Invest Ophthalmol Vis Sci 52:8442-54
Tezel, Gülgün; Yang, Xiangjun; Luo, Cheng et al. (2010) Hemoglobin expression and regulation in glaucoma: insights into retinal ganglion cell oxygenation. Invest Ophthalmol Vis Sci 51:907-19
Luo, Cheng; Yang, Xiangjun; Kain, Angela D et al. (2010) Glaucomatous tissue stress and the regulation of immune response through glial Toll-like receptor signaling. Invest Ophthalmol Vis Sci 51:5697-707

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