Publication Date

2018

Document Type

Dissertation/Thesis

First Advisor

Gaillard, Elizabeth R.

Degree Name

Ph.D. (Doctor of Philosophy)

Legacy Department

Department of Chemistry and Biochemistry

LCSH

Biochemistry

Abstract

Age-related changes to endogenous pigments in the retinal pigment epithelium (RPE) are thought to significantly contribute to the etiology and progression of retinal diseases, such as Age-related macular degeneration (AMD). The research in this dissertation studies the modulation of oxidative stress by melanin and the efficacy of accessible therapeutics in attenuating damage to the RPE. Structural and functional characteristics of RPE melanin were studied, including age-related changes in donor melanin. Young melanin provides significant protection to photo-stressed RPE cells, while aged human donor melanin is capable of pro-oxidant behavior in cells. Structural characterization of aged human donor melanin suggests oxidative degradation of the pigment over time, which may contribute to decreased antioxidant capacity. Immunomodulation by RPE melanin was also studied in conjunction with the effects of glycated extracellular matrix proteins. Results show that melanin pigmentation modulates expression of the cytokine interleukin-6 (IL-6) and suggest a novel role for melanin in regulating immune and inflammatory mechanisms in the RPE. With increasing age, the antioxidant infrastructure of the RPE declines, resulting in unregulated oxidative stress and development of diseases such as AMD. The efficacy of plant-derived antioxidants in attenuating blue-light mediated oxidative stress in RPE cells was studied. Low doses of these dietary antioxidants significantly attenuate oxidative damage to RPE cells and are an accessible supplement. Liposomal delivery of L-DOPA supplements was also studied as a treatment option for AMD. This delivery system for L-DOPA stabilizes the supplement, preventing the formation of cytotoxic oxidation products. The supplements studied can serve as low-cost, accessible therapeutics for treatment and prevention of retinal damage and disease progression. The molecular mechanisms of aging are complex and multifaceted. In the retina, changes to endogenous pigmentation overtime promote cell damage and disease progression. The functional role of melanin in the RPE is not fully understood, however the pigment appears to play a significant role in modulating oxidative stress and inflammation. A better understanding of how biochemical changes to the RPE contribute to the onset and progression of age-related disease can better the development of therapeutics and target specific treatments.

Comments

Advisors: Elizabeth R. Gaillard.||Committee members: Sherine F. Elsawa; James R. Horn; Victor Ryzhov.||Includes illustrations.||Includes bibliographical references.

Extent

182 pages

Language

eng

Publisher

Northern Illinois University

Rights Statement

In Copyright

Rights Statement 2

NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.

Media Type

Text

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