京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18850号 / 医博第3961号 / 新制||医||1007(附属図書館) / 31801 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 吉村 長久, 教授 中畑 龍俊 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Primary rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic emergencies. RRD is caused by a full thickness break in the retina which initiates separation of the neurosensory retina from the underlying retinal pigment epithelium. The subsequent accumulation of fluid within this potential space extends the area of detachment and causes visual loss. Previous assessments of RRD incidence have demonstrated large differences in case definition and methodology, with incidence estimates varying 3-fold geographically and in different time periods. To date there have been no systematic or prospective incidence estimates of primary RRD in the U.K. In this thesis I present the findings of a 2-year epidemiology study that prospectively aimed to recruit all incident cases of primary RRD diagnosed in Scotland. Case recruitment from consenting participants comprised a detailed questionnaire and a blood sample. In this thesis, I present the findings of the Scottish retinal detachment study that examined the incidence, demographic features, temporal incidence trends, as well as clinical and socio-economic associations of primary RRD in Scotland. From the clinical and genetic resource I assembled, I calculated the first population based estimate of the sibling recurrence risk ratio for RRD and designed and assisted in the analysis of the first case-control genome wide association study of this condition. Results from this study have estimated the annual incidence of primary RRD in Scotland to be 12.05 per 100,000 population. Based on this estimate, there are approximately 7,300 new cases annually in the United Kingdom. RRD incidence increases with age, is more common in men and right eyes, and is strongly associated with socio-economic affluence. In addition, using hospital episode data, the overall age-standardised incidence of RRD in Scotland was shown to be steadily increasing since 1987 with an average annual increase of 1.9%. Analysis of the clinical findings highlighted that the majority of RRD cases are caused by more than one retinal break; an important consideration for appropriate surgical management. Ocular trauma, previous cataract surgery, family history, and retinal degeneration are important predisposing features. In addition, over a 2 year period approximately 7% of individuals will suffer a RRD in the fellow eye representing an important risk of bilateral visual loss. Furthermore, I demonstrate that the risk of having an affected sibling with RRD is increased 2-fold given that one sibling has had the condition, substantiating a genetic component to the pathogenesis of this condition. In the final aspect of this thesis I will present the design and analysis of a two stage case-control genome-wide association study examining the role of common genetic variants and selected candidate genes in predisposing to RRD development.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

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Age-related macular degeneration (AMD) is the leading cause of blindness in the western world for people over 60 years of age. The most severe pathological event of AMD is choroidal neovascularization (CNV), the process of new vessel formation emerging from the choroid. The new vessels extend into the normally avascular photoreceptor cell layer, where they leak fluid and cause photoreceptor cell death. CNV is thought to be initiated by hypoxia and chronic inflammation, which occur due to abnormal, age-related changes within the retinal pigmented epithelium (RPE). These events cause increased expression of the angiogenic protein vascular endothelial growth factor (VEGF) via hypoxiainducible factor-1 (HIF-1), a transcription factor that is vital in regulation of cellular responses to hypoxic and inflammatory conditions. Increased VEGF signaling stimulates proliferation and migration of vascular endothelial cells and facilitates the neovascular process. To target the early pathological events that lead to CNV, we have engineered a novel gene therapy vector that uses HIF-1 regulation to stimulate production of an angiostatic protein, endostatin from the RPE. The purpose of this study was to characterize the activity of our hypoxiaregulated, RPE-specific promoter in vitro, and investigate the effects of regulated endostatin expression, driven by our regulated promoter, on CNV in a mousemodel. We found the regulated promoter construct has robust activity in vitro only in RPE cells, and is conditionally responsive in hypoxic conditions. / In the laserinduced CNV model, CNV area was 80% smaller (P<0.0001) in eyes treated with the hypoxia-regulated, RPE-specific endostatin vector than in untreated eyes. CNV area was equally reduced in eyes treated with an unregulated endostatin vector (CMV-endostatin). However, less endostatin protein was detected in eyes treated with the regulated vector. Since it is unknown whether broad and constitutive endostatin expression will have damaging effects within the retina, it may be safer to limit its expression to pathological conditions. We have demonstrated that local, hypoxia-regulated expression of endostatin can effectively inhibit CNV, and thus, offers the further possibility of a prophylactic treatment for neovascular AMD. / by George Wesley Tyler Smith. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.