Publication Date
2017
Document Type
Dissertation
Committee Members
Julian Gomez-Cambronero, Ph.D. (Advisor); Nancy Bigley, Ph.D. (Committee Chair); Juliusz A. Kozak, Ph.D. (Committee Member); Yong-jie Xu, M.D./Ph.D. (Committee Member); Michael Markey, Ph.D. (Committee Member); Gerald Alter, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Phospholipase D (PLD) is a cell membrane remodeling and signaling protein implicated in the pathology of chronic inflammation. As PLD is also central to macrophage cell migration, we investigated the molecular basis of PLD's involvement and regulation in macrophage-initiated inflammation (atherosclerosis) and resolution. We have found that PLD is associated with signaling proteins and positively affects cell movement, phagocytosis and NADPH-initiated release of Reactive Oxygen Species (ROS). We found that PLD2 but not PLD1 is important for foam cell formation that causes atherogenesis. We have also found a novel way of inducing macrophage class-switch (polarization) by PLD overexpression. PLD induces a macrophage M1 to M2 class-switch that accelerates resolution of inflammation and limits damage to blood vessels and affected tissues during atherosclerosis and other inflammatory conditions. We also investigated a new molecular pathway for macrophage; class-switch (M1-to-M2) by overexpressed PLD resulting in inflammation by bacterial phagocytosis or resolution of inflammation by efferocytosis. In order to understand the physiological relevance of PLD's role in inflammation and resolution, we studied the effect of resolvins, a class of specialized proresolving lipid mediators (SPMs), on PLD expression and activity in the different macrophage populations taking into consideration the time course of inflammation and resolution. We found that RvD5 upregulates PLD activity and expression in M2 macrophages confirming a molecular mechanism for PLD's role in resolution of inflammation.
Page Count
153
Department or Program
Biomedical Sciences
Year Degree Awarded
2017
Copyright
Copyright 2017, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
