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.
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.
|Sanderson, Julie; Dartt, Darlene A; Trinkaus-Randall, Vickery et al. (2014) Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res 127:270-9|
|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|
|Beckel, Jonathan M; Argall, Arthur J; Lim, Jason C et al. (2014) Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain. Glia 62:1486-501|
|Guha, Sonia; Liu, Ji; Baltazar, Gabe et al. (2014) Rescue of compromised lysosomes enhances degradation of photoreceptor outer segments and reduces lipofuscin-like autofluorescence in retinal pigmented epithelial cells. Adv Exp Med Biol 801:105-11|
|Guha, Sonia; Coffey, Erin E; Lu, Wennan et al. (2014) Approaches for detecting lysosomal alkalinization and impaired degradation in fresh and cultured RPE cells: evidence for a role in retinal degenerations. Exp Eye Res 126:68-76|
|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|
|Guha, Sonia; Baltazar, Gabriel C; Coffey, Erin E et al. (2013) Lysosomal alkalinization, lipid oxidation, and reduced phagosome clearance triggered by activation of the P2X7 receptor. FASEB J 27:4500-9|
|Li, Ang; Leung, Chi Ting; Peterson-Yantorno, Kim et al. (2012) Mechanisms of ATP release by human trabecular meshwork cells, the enabling step in purinergic regulation of aqueous humor outflow. J Cell Physiol 227:172-82|
|Xia, Jingsheng; Lim, Jason C; Lu, Wennan et al. (2012) Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors. J Physiol 590:2285-304|
|Li, Ang; Zhang, Xiulan; Zheng, Danying et al. (2011) Sustained elevation of extracellular ATP in aqueous humor from humans with primary chronic angle-closure glaucoma. Exp Eye Res 93:528-33|
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