Ocular Actions of Endothelins

  • Yorio, Thomas (PI)

Project Details


DESCRIPTION (From the Applicant's Abstract): Glaucoma is a leading cause of blindness in the U.S. and worldwide that occurs as a result of a loss in retinal ganglion cells and a progressive optic neuropathy. Identification of the causative factors leading to this disease is of great interest. Recently, it has been shown that patients with primary open angle glaucoma (POAG) have an elevation in their aqueous humor endothelin (ET) concentrations. Similarly, in a animal model of glaucoma (Beagles) a four-fold increase in endothelin is seen in the aqueous humor. Our laboratory has been investigating the role of ocular endothelins for several years and recently have shown that it may be playing a role in the pathogenesis of glaucoma based on preliminary observations of its effects on axonal transport and ET's ability to activate the NOS-2/NO pathway. The overall goal of this application is to demonstrate that endothelin is an important ocular derived peptide that is not only involved in IOP and vascular homeostasis, but is a key component in the pathogenesis of glaucoma. The hypothesis to test is that ET is preferentially synthesised and released in the eye and at increasing concentrations mediates a series of events that exert detrimental effects on optic nerve function through decreases in axonal transport and increases in neurotoxic compounds, such as NO. The net effect is to promote retinal ganglion cell death. The following aims are planned to address this hypothesis: 1) Can elevated pressure or neuronal regulation increase endothelin synthesis and release in retinal pigment epithelium (RPE), optic nerve astrocytes (ONA) and lamina cribosa (LC) cells? Is there a functional cross-talk between ET and nitric oxide (NO)? 2) What signal transduction mechanisms and transcriptional regulation sites are associated with ET synthesis following elevation of pressure, neuronal regulation or activation of the NO pathway in RPE, ONA and LC cells? 3) Does ET play a role in the optic nerve damage observed in the in vivo rat elevated pressure model? Are there changes in ET receptor expression in various ocular tissues following elevation of IOP and is there a correlation between ET aqueous concentrations to elevations in IOP? and 4) Determine the ET receptor subtype involved and the role of NO in the optic nerve damage and effects on axonal transport induced by elevated pressure or ET administration. These specific aims are designed to determine if ET contributes to the optic neuropathy associated with elevations in IOP. Ultimately these studies could provide insight into the etiology of glaucoma and propose new alternative treatments for patients with glaucoma.
Effective start/end date1/12/9830/11/06


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