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Title: Targeting Schlemm's canal endothelium to modulate aqueous humour outflow facility as a potential treatment for glaucoma
Author: Reina Torres, Ester
ISNI:       0000 0004 7656 817X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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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.
Supervisor: Overby, Darryl Sponsor: Fight for Sight ; BrightFocus Fundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral