Date of Award

2018

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Administrative Home Department

Department of Chemistry

Advisor 1

Lanrong Bi

Committee Member 1

Sarah Green

Committee Member 2

Rudy Luck

Committee Member 3

Qinghui Chen

Abstract

Generation of reactive oxygen species (ROS) constantly occurs in healthy cells and is inevitable for aerobic organisms. Controlled ROS production provides the optimal redox state for the maintaining proper cellular function. When large amounts of ROS accumulated, oxidative cellular stress occurs. Under conditions of oxidative stress, overproduction of ROS production can lead to damage to membrane lipids, proteins, and nucleic acids. Oxidative damage of these biomolecules is associated with a range of pathophysiological processes, including aging, carcinogenesis, ischemic reperfusion injury, and neuro-degenerative diseases. The pathogeneses of oxidative stress-mediated diseases are complex in nature.

Through the use of our newly synthesized fluorescent probes, the role of oxidative damage in the pathogenesis of ischemia/reperfusion injury has been updated. However, there is a need of adequately powered trials to confirm the validity of these fluorescent probes for monitoring cellular response to oxidative damage, initiation of treatment, and reliably assessing therapy efficacy. Towards this, a correlation between oxidative stress and mitochondrial dysfunction was further examined in in vitro and in vivo models of ischemia/reperfusion injury (Chapter 1). Moreover, these newly validated organelle-targetable fluorescent probes and their relevance in the detection of diseases and assessing of treatment efficacy were further investigated in the experimental models of ischemia/ reperfusion injury (Chapter 1) and cancer (Chapter 2). The overproduction of ROS can cause severe damage to cellular macromolecules, especially the DNA. It is important to develop new molecular probes for sensing DNA oxidative damage. Finally, a series of novel nucleic acid-based fluorescent probes are developed (Chapter 3) for biosensing of DNA oxidative damage to alterations in the cellular redox state during hypoxia or oxidative stress. Identification of oxidative DNA damage allows us to have better understanding of how it is implicated in a number of diseases.

For my future research direction, I am interested in developing new strategy to improve a cell’s ability to withstand oxidative damage thereby protecting its DNA. I am also interested in finding new ways to increase the activity of DNA repair genes, which may enable the genes to better handle oxidative damage.

Available for download on Tuesday, December 10, 2019

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