Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 109-154) Also available in print.

Thesis (M.S.)--The University of North Carolina at Greensboro, 2008. / Directed by Joel Bowen; submitted to the Dept. of Chemistry and Biochemistry. Title from PDF t.p. (viewed Aug. 26, 2009). Includes bibliographical references (p. 88-90).

Thesis (M.Orth.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 74-95). Also available in print.

Thesis (M.Sc.)--York University, 2009. Graduate Programme in Kinesiology. / Typescript. Includes bibliographical references (leaves 75-109). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR51528

Thesis (Ph. D.)--University of Chicago, Committee on Human Nutrition and Nutritional Biology, June 2003. / Includes bibliographical references. Also available on the Interet.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 216-255).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy

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.

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