All ETDs from UAB

Advisory Committee Chair

Stephen Barnes

Advisory Committee Members

Dale A Dickinson

Natalia Y Kedishvili

Matthew B Renfrow

Om P Srivastava

Tim M Townes

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The cataract is a common ailment affecting the aged population. It appears over time and affects the quality of one’s life by the eventual loss of vision. Currently, there is no effective strategy to prevent or treatment to reverse the development of a cataract. As well, there is no consensus on one particular mechanism or sequence of events that contributes to its formation. In order to better understand the possible etiology of the cataract, it is necessary to define the biochemical changes that occur to lens proteins as one ages, as these are the key players in the prevention of the cataract. The α–crystallin proteins are the most abundant protein class in the lens and possess a chaperone–like function sequestering denatured proteins within large protein complexes to maintain their solubility. This is essential as denatured proteins can aggregate and form light–scattering precipitates, a hallmark of a cataractous lens. This research study was performed to obtain insight into the basic biochemical characteristics of α–crystallins to better understand the balance within the lens to maintain a functional pool of these “rescue” proteins. Upregulation of expression of the α–crystallins in response to external signals from the nuclear hormone receptor pathways was examined, since it would be beneficial for lens health. Receptors are activated by their cognate hormone (such as 17ß–estradiol in the estrogen receptor pathway) and bind to their cognate DNA response element driving the expression of the downstream gene. The role of the truncation of αA–crystallin in vivo, expected to lead to reduced chaperone capabilities, was also examined. Defining regional distributions of these species in pre– and post–cataractous lenses could offer insight into how functional αA–crystallin affects lens health locally. Finally, the effects of near–UV light (a source of oxidative protein damage) on a recombinant αB–crystallin protein were determined to enable a better understanding of how this oxidation affects the structure of this protein. Taken together, these studies contribute to specific aspects of lens biochemistry that may permit the understanding of how a cataract may develop as a result of expression, localization or modification of the abundant α–crystallins.

Share

COinS