Date of Award

12-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Cell Biology and Genetics

Department

Graduate School of Biomedical Sciences

First Advisor

Patrick R. Cammarata

Abstract

Lens epithelial cells in a fully mature lens thrive in a hypoxic environment by developing several pro-survival mechanisms that can prevent cellular dysfunction. Many of these mechanisms focus on maintaining mitochondrial membrane integrity. Loss of integrity of either the inner or outer mitochondrial membrane results in the dissipation of the mitochondrial electrochemical gradient in a process termed mitochondrial membrane permeability transition (mMPT). The project herein focuses primarily on understanding the role of glycogen synthase kinase-3β (GSK-3β) in preventing mMPT in human lens epithelial (HLE-B3) cells; and, understanding that role in relation to extracellular signal-regulated kinase 1/2 (ERK1/2), a known regulator of GSK-3β activity. These studies further define mitoprotective mechanisms of lens cells by identifying how ERK1/2 and GSK-3β can directly (through the mitochondrial transition pore) or indirectly (through the induction of apoptosis) effect mitochondrial membrane potential). Additionally, we extended the GSK-3β studies into the field of epithelial to mesenchymal transition (EMT) research. Specifically we focused on understanding how GSK-3β in conjunction with the hypoxia inducible factor (HIF) proteins can influence the persistence of EMT and the production of vascular endothelial growth factor (VEGF). Collectively, these studies demonstrate important roles in lens epithelial cell mitoprotection for GSK-3β and ERK1/2; and, demonstrate a pivotal role for HIF-1α in the persistence of EMT under hypoxic conditions. Overall, the work described herein has provided invaluable information and understanding in the field of mitoprotection research as well as EMT research.

Comments

Brooks, Morgan Madison, The role of glycogen synthase kinase-3β in the regulation of mitochondrial membrane permeability. Doctor of Philosophy (Cell Biology) November, 2014, 120 pages, 21 illustrations, bibliography, 80 titles. Available worldwide December 2015