Browsing by Subject "lenticular mitoprotection"
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Item The Disadvantageous Interrelationship between Lenticular Mitoprotection and Epithelial-Mesenchymal transition via Nuclear Beta catenin(2014-12-01) Neelam, Sudha; Patrick R. CammarataThe human lens epithelium thrives in a naturally hypoxic environment resisting mitochondrial depolarization, a precursor of apoptosis. The ability of the lens to resist mitochondrial depolarization is referred to as lenticular mitoprotection and is rendered by a sustained synthesis of the pro-survival Vascular Endothelial Growth Factor (VEGF). Similar lenticular mitoprotective pathways come in to play when the hypoxic lens epithelium is exposed to atmospheric oxygen during ocular surgeries like the cataract surgery. Posterior capsular opacification (PCO) is a complication of cataract surgery resulting from the mesenchymal transition of the epithelial cells. The lenticular mitoprotective pathways involved in lens epithelial cell survival also initiate the mesenchymal transition of the epithelial cells, thus contributing to the pathogenesis of PCO. The progression of PCO involves the initiation phase in atmospheric oxygen (during the cataract surgery) and a persistence phase (persistence of the insult which occurred during cataract surgery) in hypoxia. The initial insult to epithelial cells occurs in atmospheric oxygen initiating the mesenchymal transition which persists when the lens epithelium is back in hypoxia after the surgery. Isolating the two events of lenticular mitoprotection and mesenchymal would be a beneficial therapeutic target. The data presented in this study supports a model whereby the onset of epithelial to mesenchymal transition may circuitously benefit from the enhanced synthesis of the pro-survival factor VEGF. As a result of which a mesenchymal cell resisting mitochondrial depolarization is generated, leading to the progression of PCO. The findings in this study support the possibility of generating a therapeutic target such that the mesenchymal transition of normal epithelial cells can be prevented without affecting the levels of pro-survival VEGF and compromising the lenticular mitoprotective pathways.Item The Role of Glycogen Synthase Kinase-3β in the Regulation of Mitochondrial Membrane Permeability(2014-12-01) Brooks, Morgan M.; Patrick R. CammarataLens 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.