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Aqueous humour outflow dynamics in mice

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Title: Aqueous humour outflow dynamics in mice
Authors: Madekurozwa, Michael
Item Type: Thesis or dissertation
Abstract: Glaucoma is the leading cause of irreversible blindness worldwide. The major risk factor of glaucoma is sustained elevation of intraocular pressure (IOP), and lowering IOP is the only proven method for halting the progression of glaucomatous blindness. IOP is determined by the balance between aqueous humour (AH) production and drainage through pressure-dependent and pressure-independent outflow pathways. Elevated IOP is caused by increased hydraulic resistance through the pressure-dependent outflow pathway. Most glaucoma therapies aimed at lowering IOP do not effectively target pressure-dependent outflow due to an incomplete understanding of its regulation. We aim to use mice to study outflow regulation in the context of glaucoma. Mice are commonly used to study IOP regulation due to their resemblance to human ocular anatomy, genetics and pharmacology. However, while the bulk of AH drainage passes through the pressure-dependent pathway in humans, it has been reported to predominantly flow through the pressure-independent pathway in mice, which if true would invalidate the mouse as a model for studying outflow as occurs in humans. Here we present the first direct measurement of pressure-independent outflow in mice, showing it to be indistinguishable from zero which supports the mouse being a good model for pressure-dependent outflow as occurs in humans. We also investigated the role of the ocular pulse in outflow facility regulation, which arises due to cardiac pulsations in ocular blood volume. To do this we designed an apparatus to apply a sinusoidal pressure waveform superimposed onto a steady pressure whilst simultaneously measuring outflow resistance. We show that the ocular pulse leads to immediate decrease in outflow resistance in mice, and the effect was partly mediated through nitric oxide synthase. Finally, we developed a new apparatus and method to measure outflow resistance in living mice accounting for the influence of anaesthesia that introduces time-dependent changes in AH physiology.
Content Version: Open Access
Issue Date: Oct-2018
Date Awarded: Apr-2019
URI: http://hdl.handle.net/10044/1/88851
DOI: https://doi.org/10.25560/88851
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Overby, Darryl R.
Sherwood, Joseph M.
Sponsor/Funder: Imperial College London
BrightFocus Foundation
National Institutes of Health (USA)
Funder's Grant Number: G2015145
Department: Bioengineering
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Bioengineering PhD theses