|Title:||Potential drug treatments for Müller cell dysfunction|
|Publisher:||University of Sydney.|
Clinical Ophthalmology and Eye Health.
Western Clinical School
|Abstract:||The term glia, from the Greek word ‘glue’, reflects the misguided view that glia (Müller cells, astrocytes and microglia) merely serve as functionally inert neuronal support structures, an opinion that remained prevalent for over a century. Our group recently developed a transgenic mouse model in which Müller cells can be selectively and inducibly ablated, which results in photoreceptor apoptosis and reactive activation of surviving Müller cells. Using this model, my studies aimed to 1) Characterise endogenous intraretinal cell signalling changes that occur following selective Müller cell ablation (both expression and localisation); 2) Identify potential therapeutics for Müller cell dysfunction based on significantly altered signalling cascades following selective Müller cell ablation and 3) Assess the ability of multiple therapeutics to protect photoreceptors following Müller cell dysfunction. Selective Müller cell ablation in mice induced profound alterations in intraretinal cell signalling, particularly the expression, and localisation, of the Interleukin-6/glycoprotein130 (IL-6/gp130) family of cytokines and downstream effectors. Ciliary Neurotrophic Factor (CNTF), Leukaemia Inhibitory Factor (LIF) and 8-hydroxy-2-(di-n-propylamino)-tetralin (8–OH–DPAT) were chosen in an attempt to correct the defective endogenous cell signalling, which had been characterised following selective Müller cell ablation, and inhibit photoreceptor degeneration. CNTF and 8-OH-DPAT conferred photoreceptor protection, in contrast to LIF. These findings have both basic and applied clinical implications: endogenous cell signalling changes following selective Müller cell ablation may shed light on intraretinal signalling changes that result from Müller cell dysfunction. Müller cells appear crucial for the functional benefits of LIF and potentially other IL-6/gp130 cytokines. Further elucidation of IL-6/gp130 cytokine signalling, and the role played by Muller cells in both the healthy and diseased retina, raises the hope that future treatments will be preventative, not suppressive, and promote repair rather than destruction.|
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|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|COOREY Nathan - Final Thesis.pdf||2.89 MB||Adobe PDF|
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