Interplay Between Oxidative Stress, PAX6 And The Immune Response In The Developing Eye

Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor

Vasiliou, Vasilis

Abstract

Eye development and lens morphogenesis are complex processes that are carefully orchestrated by a multitude of factors including extracellular signals, local activators and signal-regulated DNA-binding transcription factors. Any perturbation to these factors can impair eye development and lens morphogenesis and result in a range of structural abnormalities of the lens (and other ocular structures) and a spectrum of human disease ranging from the complete absence of the eye (anophthalmia), reduced eye size (microphthalmia) or optic fissure closure defect (coloboma). Oxidative stress, an imbalance between oxidants (e.g., reactive oxygen species (ROS)) and antioxidants (e.g., glutathione) in favor of the oxidants, may disrupt the development of many tissues by interrupting signaling cascades. The hyperproduction of ROS can serve as secondary messengers and altering the function of proteins, including DNA-binding transcription factors, through oxidation. Despite this knowledge, little is known about the role of oxidative stress during lens development. This dissertation is comprised of three papers, which collectively explore the role of the oxidative stress in lens development and disease.In the first study (Chapter 2), we aimed to describe the requirement of the retinoic acid signaling pathway for life and eye development. To accomplish this, we used the ExAC database and extensively reviewed the literature to place our data mining results into context. These findings have been published (PMID: 31796115). In the second study (Chapter 3), we aimed to describe the role of oxidative stress in regulating eye and lens development in a genetically modified mouse model in which oxidative stress is induced in the lens through the conditional deletion of Gclc, a gene that encodes the catalytic subunit for the production of glutathione (GSH). In this aim, we describe how lens development and the function of a critical transcription factor, paired box 6 (PAX6), are impaired by oxidative stress. These findings have been published (PMID: 34425299). In the last study (Chapter 4), we further explored our unexpected finding that upon deletion of Gclc in the developing lens, inflammation of lens cells is induced. We use our Gclc-null mouse model, ex vivo and in vitro systems to further describe how oxidative stress induces inflammation of lens epithelial cells. The data presented in this chapter is supported by the reports that lens epithelial cells initiate an inflammatory response following mock cataract surgery in mice. These findings will soon be submitted to a Chemico-Biological Interactions for review. Collectively, the findings presented within this dissertation significantly advance our understanding of eye development by providing evidence for a role of oxidative stress and indicating that oxidative stress promotes inflammation of lens cells. It is hoped that these results will have an outsized impact on public health by suggesting that mitigation of and/or prevention of oxidative stress may be a viable therapeutic strategy for diseases of eye development and prevention of secondary cataract, a common complication of cataract surgery.

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