Defense Date

3-27-2009

Graduation Date

Fall 2009

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology-Toxicology

School

School of Pharmacy

Committee Chair

Vicki Davis

Committee Member

Jane Cavanaugh

Committee Member

Carmen Colitz

Committee Member

Kyle Selcer

Committee Member

Paula Witt-Enderby

Keywords

Cataract, Estrogen Receptor, Human, Lens, Mouse

Abstract

The increased risk of age-related cataracts in postmenopausal women and studies in animal models suggest that estrogen may have a protective role in the lens. However, very little is known regarding the role of estrogen and its receptors in the lens. To begin unraveling the estrogen signaling mechanism in the lens, the following aims were investigated: 1) to determine if estrogen receptors are expressed in the lens, [125I]-17beta-estradiol binding and mRNA expression of ERalpha, ERbeta, and GPR30 were examined in the mouse and human lens; 2) to determine if the loss of ERalpha and/or ERbeta receptors will induce spontaneous development of cataracts and to examine their role in an inducible cataract model; and 3) to identify estrogen-regulated genes in the lens that influence cataract development in the ERdelta3-induced cataract model. High-affinity, saturable binding sites for 17beta-estradiol were identified in the nuclear, cytosolic, and membrane fractions of the mouse and human lens. Additionally, detectable binding in the membrane fraction and expression of GPR30 mRNA in the mouse and human lens are the first evidence of this novel transmembrane estrogen receptor in the lens of any species. Transcripts for ERalpha, ERbeta, and GPR30 were expressed in the mouse lens which suggests that one or more of these estrogen receptor subtypes are responsible for the binding detected. With the loss of nuclear ER in the lens, spontaneous cataracts did not occur; however, diminished levels or loss of ERalpha in ERdelta3 female mice increased the severity of cortical cataracts with age. These results suggest that ERalpha in the lens may provide protection against the progression of cataracts in the ERdelta3 model. Together with the cataract induction and gene expression studies, six genes were identified to be differentially expressed with estrogen versus vehicle treatment in the lenses of ERdelta3 mice. The pax6, tcfap2a, tgfbeta2, six3, sox2, and pdgfalpha genes are known to have a critical role in lens development, proliferation, differentiation and maintenance of lens homeostasis. Therefore, future examination of these genes and their pathways in the lens may contribute to the understanding of the mechanisms of estrogen-mediated protection of lens transparency. Knowledge of pathways that function to maintain lens transparency and how estrogen regulated these pathways will assist in the development of estrogen therapies that can be clinically used to delay the onset and/or progression of cataracts.

Format

PDF

Language

English

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