Glaucoma is a major cause of blindness in the world and is characterized by a loss of retinal ganglion cells. Although the disease is closely associated with elevated intraocular pressure (IOP), it is unclear how this pressure leads to cell death. This proposal is based upon the novel hypothesis that elevated IOP triggers the release of ATP which over-stimulates cytotoxic P2X7 receptors on retinal ganglion cells. Evidence for pressure-dependent ATP release will be confirmed using rat models of glaucoma, while the toxic effects of P2X7 receptor stimulation will be determined in vivo. The pre-apoptotic genes activated by both approaches will be characterized and compared to identify the purinergic component of the response to pressure in vivo. The mechanisms underlying the release of ATP and of P2X7 receptor stimulation will be probed on a cellular level. The role of pannexin hemichannels in the ATP release that accompanies ganglion cell stretch and swelling will be determined, and the ability of this released ATP to autostimulate P2X7 receptors on ganglion cells will be evaluated by recording intracellular calcium levels and whole cell ion currents. Combining in vivo evidence for excess ATP with the identification of the responsible mechanisms ensures this proposal will be both innovative and relevant, providing new insight into how increased pressure damages ganglion cells in glaucoma.

Public Health Relevance

This project is based on the hypothesis that retinal ganglion cells are damaged in glaucoma by pressure-dependent release of excess ATP into the retina which stimulates P2X7 receptors on retinal ganglion cells. This proposal will confirm this relationship and explore how this pathological release occurs with the aim of preventing the initial stages of damage in glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015537-07
Application #
8212109
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2004-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$519,902
Indirect Cost
$194,963
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Beckel, Jonathan M; Lu, Wennan; Civan, Mortimer M et al. (2016) Treatment of Retinal Disorders with Purinergic Drugs: Beyond Receptors. J Ocul Pharmacol Ther 32:488-489
Mitchell, Claire H; Stamer, W Daniel (2016) Dedication of Special Issue on Purinergic Regulation in the Eye to Mortimer M. Civan. J Ocul Pharmacol Ther 32:484
Lu, Wennan; Hu, HuiLing; Sévigny, Jean et al. (2015) Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. Invest Ophthalmol Vis Sci 56:3075-83
Maguire, Sarah E; Rhoades, Seth; Chen, Wen-Feng et al. (2015) Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis. J Biol Chem 290:20407-16
Beckel, Jonathan M; Daugherty, Stephanie L; Tyagi, Pradeep et al. (2015) Pannexin 1 channels mediate the release of ATP into the lumen of the rat urinary bladder. J Physiol 593:1857-71
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Coffey, E E; Beckel, J M; Laties, A M et al. (2014) Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer's disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience 263:111-24

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