Ocular Actions of Endothelins

  • Yorio, Thomas (PI)

Project Details

Description

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.
StatusFinished
Effective start/end date1/12/9830/11/06

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