Document Type

Dissertation

Date of Degree

Spring 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Robert F. Mullins

Second Advisor

Todd E. Scheetz

Abstract

An estimated 170.38 million elderly adults suffer from some stage of age-related macular degeneration (AMD) worldwide, a vision defect that damages the macula, the central region of the retina required for sharp vision, such as reading, driving, and recognizing faces. Genetic factors strongly modify one's risk for developing AMD, and most of these genetic changes are found in genes of the alternative complement cascade, a component of the immune system. The lack of effective AMD prevention calls for the identification of druggable molecules and pathways.

In my research, I use microarrays and RNA sequencing to investigate the events occurring in early AMD, the reasons for macular susceptibility to AMD, and the events triggering aberrant blood vessel growth in late AMD. First, I found that genes associated with endothelial cells tend to be expressed at lower levels in human donors eyes affected by early AMD than in control eyes, concordant with previous studies indicating loss of choriocapillaris in early AMD. Second, I found that molecular signals across regions of the retina, retinal pigment epithelium, and choroid generally mirror the distribution of cell types in these regions. Third, I found that damage to cultured primate chorioretinal endothelial cells by the end product of complement activation, membrane attack complex, produces an environment conducive to choroidal neovascularization, a symptom of late-stage AMD. I propose a model that bridges genetic variants in the complement cascade genes with blood vessel loss in early AMD and the pathological growth of blood vessels in late AMD.

Public Abstract

Imagine having a vision defect that impairs your ability to read, drive, and recognize faces. An estimated 170.38 million elderly adults suffer from some stage of age‑related macular degeneration (AMD) worldwide. This disease damages the macula, the central region of the retina required for sharp vision. Genetic factors strongly modify one’s risk for developing AMD, and most of these genetic changes are found in genes of the alternative complement cascade, a component of the immune system. The lack of effective AMD prevention calls for the identification of druggable molecules and pathways.

I use molecular tools to investigate the events occurring in early AMD, the reasons for macular susceptibility to AMD, and the events triggering aberrant blood vessel growth in late AMD. First, I found that genes associated with blood vessels tend to be expressed at lower levels in human donors eyes affected by early AMD than in control eyes, concordant with previous studies indicating loss of these cells in early AMD. Second, I found that molecular signals across regions of the eye (retina, retinal pigment epithelium, and choroid) generally mirror the distribution of cell types in these regions. Third, I found that damage to primate blood vessel cells by activation of complement produces an environment conducive to aberrant growth of blood vessels, a symptom of late‑stage AMD. I propose a model that bridges genetic variants in the complement cascade genes with blood vessel loss in early AMD and the pathological growth of blood vessels in late AMD.

Keywords

publicabstract, age-related macular degeneration, choroid, gene expression, retina, retinal pigment epithelium, RNA sequencing

Pages

xx, 179 pages

Bibliography

Includes bibliographical references (pages 151-179).

Comments

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Copyright

Copyright 2015 Steven Scott Whitmore

Included in

Genetics Commons

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