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Revised dissertation 04-4-17.pdf (7.17 MB)

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Lens Adaptation to Glutathione Deficiency: Implications for Cataract

Whitson, Jeremy A
http://rave.ohiolink.edu/etdc/view?acc_num=case1491482909327594

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Pathology.
The antioxidant glutathione (GSH) protects lens proteins from post-translational modifications that result in their aggregation and cataract formation. With age, the human lens becomes increasingly depleted of GSH, which contributes to the development of age-related cataract. In order to gain a comprehensive understanding of the role of GSH in the pathogenesis of age-related cataract, I set out to study the consequences of and adaptations to GSH-deficiency in the lens using the Lens Glutathione Synthesis Knockout (LEGSKO) mouse model of cataract. The questions addressed in this thesis are: 1) How does the LEGSKO lens maintain >1 mM GSH despite a complete lack of GSH synthesis? and 2) What gene expression and signaling changes are associated with lens GSH deficiency? The first of these questions was addressed by measuring lens uptake of isotopically-labeled GSH using an LC-MS/MS system. I determined that mouse lenses obtain exogenous GSH in two ways: from the aqueous humor via an active transport mechanism and from the vitreous humor via passive diffusion. It was found that mouse eyes have a high concentration of GSH in their vitreous humor and a low concentration of GSH in their aqueous humor and, because of this, nearly all the GSH in the LEGSKO lens is derived from equilibration with the vitreous pool. It was also found that the eyes of humans and other large animals lack this high vitreous GSH concentration. The second question of this thesis was addressed by comparing the transcriptomic profiles of wild-type control lenses, chronically GSH-deficient LEGSKO lenses, and acutely/severely GSH-deficient buthionine sulfoximine-treated (BSO;GSH synthesis inhibitor) LEGSKO lenses using RNA-Seq technology. These data show that the most robust responses to GSH-deficiency in the lens are upregulation of detoxifying genes, including metallothioneins, aldehyde dehydrogenases, and carboxylesterase, activation of epithelial-mesenchymal transition (EMT) signaling, and alterations to lipid homeostasis and transport systems. These findings suggest that GSH plays a role in EMT-mediated posterior secondary cataract and implicate new potential targets for cataract therapeutics. This body of work greatly expands knowledge of the benefits and regulation of GSH in the lens, consequences of its loss, and other genes which promote lens clarity.
Vincent Monnier (Advisor)
Xingjun Fan (Advisor)
Alan Tartakoff (Committee Chair)
John Mieyal (Committee Member)
Maria Hatzoglou (Committee Member)
Xiongwei Zhu (Committee Member)
Clive Hamlin (Committee Member)
208 p.
Biology; Biomedical Research; Pathology
cataract, glutathione, EMT, lens, transcriptome, homeostasis

Recommended Citations

Citations

  • Whitson, J. A. (2017). Lens Adaptation to Glutathione Deficiency: Implications for Cataract [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1491482909327594

    APA Style (7th edition)

  • Whitson, Jeremy. Lens Adaptation to Glutathione Deficiency: Implications for Cataract . 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1491482909327594.

    MLA Style (8th edition)

  • Whitson, Jeremy. "Lens Adaptation to Glutathione Deficiency: Implications for Cataract ." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491482909327594

    Chicago Manual of Style (17th edition)

case1491482909327594
1,011
© 2017, some rights reserved.Creative Commons License Lens Adaptation to Glutathione Deficiency: Implications for Cataract by Jeremy A Whitson is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.