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Type: Thesis
Title: Manipulation of photoreceptor energy metabolism for clinical advantage
Author: Narayan, Daniel Sanju
Issue Date: 2018
School/Discipline: Adelaide Medical School
Abstract: Photoreceptors are metabolically active cells that account for the majority of the energy consumption in the retina. Photoreceptors also display high rates of aerobic glycolysis which is unusual in non-proliferating cells. Many diseases of the retina involve degeneration of photoreceptors. Retinitis pigmentosa is the most commonly encountered hereditary retinal dystrophy, featuring degeneration of rod photoreceptors followed by cone photoreceptors. The genetic mutations in retinitis pigmentosa are exclusively expressed in rods, and the secondary death of cones likely involves a component of energy failure. The overriding premise of this thesis was to further our understanding of photoreceptor energy metabolism, then manipulate photoreceptor energy metabolism for clinical advantage using an in vivo model of retinitis pigmentosa. The current thesis comprises three main experiments. In the first experiment, we investigated the role of glucose in the mouse retina and sought to provide an explanation for the high rate of aerobic glycolysis. This was performed by observing the distribution of carbon-14 glucose in the mouse retina using autoradiographic methods. In the second experiment, we characterized the temporal and spatial distribution of cone degeneration in a mouse model of retinitis pigmentosa. Cone quantification was performed using immunohistochemistry and reverse transcription polymerase chain reaction. In the third experiment, we tested two novel bio-energetic agents on the previously characterized mouse model of retinitis pigmentosa. Mice received either systemic creatine, delivered orally, or local glucose, delivered via repeated subconjunctival injection, and the effect on cone survival was measured using immunohistochemistry and neuro-behavioral responses. The results revealed that local glucose injections had no protective effect on cone survival. However, oral creatine treatment preserved cones and improved neuro-behavioral responses in retinal degeneration mice. Therefore, we demonstrated that cone degeneration in retinitis pigmentosa likely occurs due to a mechanism that involves, at least in part, energy failure. Bio-energetic treatments, such as creatine, may play a role as future therapies for retinitis pigmentosa. Further studies will be performed to elucidate the precise mechanisms through which creatine exerts its protective effects, prior to developing a pathway to clinical translation in human patients.
Advisor: Casson, Robert
Chidlow, Glyn
Wood, John
Dissertation Note: Thesis (MPhil) -- University of Adelaide, Adelaide Medical School, 2018
Keywords: Ophthalmology
energy metabolism
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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