Glaucoma is a major cause of blindness worldwide and is characterized by a series of pathological changes to optic nerve head astrocytes and retinal ganglion cells that eventually lead to vision loss. While the biggest risk factor for cell injury is elevated intraocular pressure (IOP), proinflammatory cytokines also contribute to the chronic disease. The mechanisms connecting physical strain to the cytokine response are unclear, however. This proposal is based upon the novel hypothesis that extracellular ATP links mechanical strain to the enhanced cytokine response in glaucoma. In particular, the mechanosensitive release of ATP through pannexin channels on optic nerve astrocytes can autostimulate adjacent P2X7 receptors, upregulating cytokine expression on a molecular level and activating cytokine release through both the inflammasome and classic release pathways. Using in vivo models of elevated IOP and in vitro models of cell stretch, we will demonstrate the mechanisms linking strain and inflammation and identify points of intervention.
Aim 1 will confirm the involvement of cytokines IL-1? and IL-6 in models of chronic and acute glaucoma. The time course of cytokine activation will be determined and the relative contribution of proinflammatory signals in older animals will be assessed. The contribution of pannexin and P2X7 channels will be explored on a molecular level with knockout mice, and on a pharmacological level with channel blockers;the ability of antagonists to reduce inflammasome activation may identify new treatments.
In Aim 2, the mechanisms connecting mechanical strain, ATP and cytokines will be confirmed in optic nerve head astrocytes while the effects of inflammasome product IL-1? on retinal ganglion cell health will be determined. In summary, this proposal will demonstrate that purinergic signaling links elevated IOP with the enhanced inflammatory response in astrocytes and pathology in retinal ganglion cells. This novel approach will advance our understanding of the disease on a mechanistic level while identifying possible new targets for intervention.

Public Health Relevance

Glaucoma is a major cause of blindness. This project will investigate how the increased intraocular pressure of glaucoma leads to increased inflammatory signaling in the posterior eye, determine if this link increases with age, and test the ability of drugs to prevent this response.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015537-08A1
Application #
8651585
Study Section
(DPVS)
Program Officer
Chin, Hemin R
Project Start
2004-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mitchell, Claire H; Civan, Mortimer M (2016) Introduction to Purinergic Regulation in the Eye Special Issue. J Ocul Pharmacol Ther 32:485
Lim, Jason C; Lu, Wennan; Beckel, Jonathan M et al. (2016) Neuronal Release of Cytokine IL-3 Triggered by Mechanosensitive Autostimulation of the P2X7 Receptor Is Neuroprotective. Front Cell Neurosci 10:270
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
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
Tordoff, Michael G; Aleman, Tiffany R; Ellis, Hillary T et al. (2015) Normal Taste Acceptance and Preference of PANX1 Knockout Mice. Chem Senses 40:453-9
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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