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Assessment and modulation of gliosis in inherited eye disease and its impact on cell replacement therapy

Graca, AB; (2017) Assessment and modulation of gliosis in inherited eye disease and its impact on cell replacement therapy. Doctoral thesis , UCL (University College London). Green open access

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Abstract

In most inherited retinal degenerations such as age-related macular degeneration, death of photoreceptors leads to irreversible vision impairment. As the retina starts to degenerate, the retinal environment begins to remodel. While variations in the timing and magnitude of retinal response have been reported by various studies looking at different initiating insults, there has been no comparative assessment of the diseased retinae across time in multiple models of retinal degeneration. Here, the process of gliosis, outer nuclear layer cytoarchitecture and integrity of the outer limiting membrane (OLM) were examined in seven different mouse models of inherited retinal degeneration. Findings from this study demonstrated that each of the examined mutants manifests a unique pattern of alterations occurring in the retinal microenvironment, including significant changes to OLM junctions. Moreover, these animals showed that the type of the Müller glial response and its magnitude are not correlated with disease severity. Having identified marked but varied changes in the expression of GFAP, Vimentin and chondroitin sulphate proteoglycas (CSPGs) between different models, further work investigated whether it is possible to prevent or manipulate these changes. By knocking down expression of GFAP and Vimentin by with RNA interference (RNAi), the role of these proteins both in the development of degeneration-associated glial hypertrophy and in influencing photoreceptor transplantation outcome was assessed. Consistent with the idea that CSPGs deposition in the subretinal space represents a barrier to therapeutic interventions, an enzymatic approach was used to effectively digest these molecules in a diseased mouse retina. In the last instance, RNAi-mediated knockdown of CRB1, one of the key regulators of AJs, was used to introduce disruption of OLM integrity. The overall aim of this thesis was to provide a better understanding of the barriers in a diseased retinal environment and how they can be manipulated to ease in a future some of the therapeutic strategies to help to restore lost vision.

Type: Thesis (Doctoral)
Title: Assessment and modulation of gliosis in inherited eye disease and its impact on cell replacement therapy
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
URI: http://discovery.ucl.ac.uk/id/eprint/1541540
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