Zhen Wang

Publication Date


Document Type


First Advisor

Gaillard, Elizabeth R.

Degree Name

Ph.D. (Doctor of Philosophy)

Legacy Department

Department of Chemistry and Biochemistry


Retinal degeneration--Pathogenesis


Age-related deterioration in the retinal pigment epithelium (RPE) is thought to play a central role in the development of age-related macular degeneration (AMD). The research presented in my dissertation studied the mechanisms of damage to RPE cells caused by a major chromophore of RPE lipofuscin, A2E, and by alterations in Bruch's membrane. The cytotoxicity of A2E has been studied and the data indicate that A2E has an adverse effect on RPE cells when its accumulation reaches a certain threshold. In addition, irradiation with blue light significantly increases A2E-mediated damage. A2E was found to undergo oxidation in RPE cells. The structural characterization of A2E oxidation products reveals that the oxidation of A2E results in the formation of relatively stable furanoid oxides and very reactive aldehydes. The antioxidant properties of melanin have also been studied and melanin is found to significantly inhibit A2E oxidation. Our studies also demonstrate that the antioxidant properties of melanin decrease with age, which may cause aged RPE cells to be more susceptible to oxidative stress. An increasing amount of evidence has implicated the involvement of inflammation in AMD. During inflammation, an excessive amount of nitrite is produced. We studied the nitrite-mediated modifications to extracellular matrix proteins in Bruch's membrane. Nitrite-modified proteins have increased visible light absorption, fluorescence, and cross-linking. Nitrite is also found to modify tyrosine residues of proteins leading to the formation of 3-nitrotyrosine. Modifications to the extracellular matrix proteins have deleterious effects on RPE cells, including the inhibition of RPE cell attachment, proliferation, and differentiation as well as an increase in RPE apoptosis and necrosis. Multiple factors are believed to be involved in the pathogenesis of AMD including both aging and the pathological changes. The damaging interplay between the RPE cells and Bruch's membrane appears to have an important role in the development of this disease. Many questions regarding the pathogenesis of AMD remain unanswered. Better knowledge of the biochemical and cellular changes in the aged RPE cells and Bruch's membrane will help to offer new therapeutic approaches to the treatment of AMD.


Includes bibliographical references (pages [202]-225).


xiv, 225 pages (some color pages)




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