Targeting Schlemm’s canal endothelium to modulate aqueous humour outflow facility as a potential treatment for glaucoma
File(s)
Author(s)
Reina Torres, Ester
Type
Thesis
Abstract
Glaucoma is an ocular neurodegenerative disease generally associated to sustained
elevated intraocular pressure (IOP). Lowering IOP is the only suitable therapeutic
strategy for glaucoma but current treatments do not target the root cause of elevated IOP:
increased aqueous humour outflow resistance.
The mechanisms involved in outflow resistance generation are not fully understood.
It is thought that resistance is generated at the vicinity of the juxtacanalicular
connective tissue, the inner wall of Schlemm’s canal (SC) and its basement membrane.
We hypothesise that the continuity of SC endothelium, and especially its pores, are key
regulators of outflow resistance. To test this hypothesis, we assessed the role of physiological
processes known to be relevant for pore formation by measuring changes in outflow
facility (C) using the newly developed iPerfusion system.
First, we showed that vascular endothelial growth factor (VEGF) is involved in C
regulation and that steroid-treated mice have altered VEGF signaling, potentially contributing
to outflow dysfunction and ocular hypertension. Second, we demonstrated that
down regulation of plasmalemmal vesicle-associated protein results in reduced C, probably
because of impaired ability to form intracellular pores. Third, we proved that the
inhibition of tight junction related proteins results in increased C and lower IOP. Additionally,
we also examined the effects of anesthetics on IOP and we propose a new protocol
to measure IOP by rebound tonometry.
Altogether, these studies support the idea that the inner wall of SC plays a crucial
regulatory role in aqueous humour outflow resistance. Therefore, targeting SC endothelium
and more precisely the mechanisms of pore formation may provide a new therapeutic
approach for ocular hypertension.
elevated intraocular pressure (IOP). Lowering IOP is the only suitable therapeutic
strategy for glaucoma but current treatments do not target the root cause of elevated IOP:
increased aqueous humour outflow resistance.
The mechanisms involved in outflow resistance generation are not fully understood.
It is thought that resistance is generated at the vicinity of the juxtacanalicular
connective tissue, the inner wall of Schlemm’s canal (SC) and its basement membrane.
We hypothesise that the continuity of SC endothelium, and especially its pores, are key
regulators of outflow resistance. To test this hypothesis, we assessed the role of physiological
processes known to be relevant for pore formation by measuring changes in outflow
facility (C) using the newly developed iPerfusion system.
First, we showed that vascular endothelial growth factor (VEGF) is involved in C
regulation and that steroid-treated mice have altered VEGF signaling, potentially contributing
to outflow dysfunction and ocular hypertension. Second, we demonstrated that
down regulation of plasmalemmal vesicle-associated protein results in reduced C, probably
because of impaired ability to form intracellular pores. Third, we proved that the
inhibition of tight junction related proteins results in increased C and lower IOP. Additionally,
we also examined the effects of anesthetics on IOP and we propose a new protocol
to measure IOP by rebound tonometry.
Altogether, these studies support the idea that the inner wall of SC plays a crucial
regulatory role in aqueous humour outflow resistance. Therefore, targeting SC endothelium
and more precisely the mechanisms of pore formation may provide a new therapeutic
approach for ocular hypertension.
Version
Open Access
Date Issued
2016-01
Date Awarded
2016-04
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Overby, Darryl
Sponsor
Fight for Sight (Organization)
BrightFocus Fundation
Grant Number
Ref 1385
G2013-0248
Publisher Department
Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)