Paul A. Mueller Sucessfully Defends Dissertation
On Monday, May 16, 2016 Paul A. Mueller successfully defended his dissertation titled:
"PPAP2B EXPRESSION LIMITS LESION FORMATION IN MURINE MODELS OF ATHEROSCLEROSIS”
Abstract of Dissertation
Coronary artery disease (CAD) is the leading cause of death in both men and women worldwide and is defined as a narrowing of the coronary arteries due to accumulation of atherosclerotic plaques. Genome-wide association studies have identified risk loci within the gene PPAP2B that confers a 17% increase in risk of developing CAD. Evidence suggests these aforementioned SNPs are regulating PPAP2B expression in a cis-manner through the interruption of transcription factor binding sites. PPAP2B encodes the lipid phosphate phosphatase 3 enzyme that plays a key role in degrading bioactive lysophosphatidic acid (LPA). LPA has a plethora of effects on vascular tissue and is implicated in increasing inflammation and exacerbating the development of atherosclerotic lesions in mice. Interestingly, PPAP2B expression is increased in murine models of atherosclerosis and both global and smooth muscle cell-specific deletion increases the development of lesions compared to control mice. LPP3-deficient mice with increased atherosclerosis show significant increases in LPA accumulation in their proximal aorta as well as increased expression of inflammatory markers and positive staining for leukocyte marker CD68. Globally deficient mice also show substantial increases in ICAM-1 staining in their aortic root lesions relative to controls. Preliminary evidence also suggests that total LPA content, and specifically unsaturated LPA species, increase in the atherogenic LDL-C fractions of plasma in hyperlipidemic mice prone to developing atherosclerosis. Taken together, these data suggest that as CAD develops, LPA accumulates in atherosclerotic plaques, and the intrinsic mechanism of defense is to upregulate LPP3 through transcription factor-mediated effects on PPAP2B; however, individuals harboring the previously mentioned risk alleles are unable to increase PPAP2B expression and thus experience unchecked inflammation and exacerbated development of atherosclerosis.
KEYWORDS: Lipid phosphate phosphatase 3 (LPP3), Lysophosphatidic acid (LPA), genome-wide association studies (GWAS), inflammation, low density lipoproteins (LDLC)
Doctoral Committee Members
Dr. Susan Smyth, Department of Physiology
Dr. Andrew Morris, Department of Pharmacology & Nutritional Sciences
Dr. Stefan Stamm, Department of Molecular & Cellular Biochemistry
Dr. Steve Estus, Department of Physiology
Dr. Alan Daugherty, Department of Physiology
Outside Examiner
Dr. Elizabeth Debski, Department of Biology
Acknowledgements
First and foremost I would like to thank my mentor Dr. Susan Smyth for her guidance and support over the course of my studies at the University of Kentucky. Her mentorship has been integral to my development as an independent scientist. Dr. Smyth’s patience and her passion for both quality and impactful research exemplify the role of a physician-scientist and I consider myself extremely fortunate for the opportunity to have her as my doctoral advisor all these years. I would also like to extend my gratitude to Dr. Andrew Morris who has provided his expertise, guidance and bravado throughout the years as well.
Additionally, I would like to thank my Dissertation Committee members, Dr. Alan Daugherty, Dr. Steve Estus, and Dr. Stefan Stamm for their advice and intellectual guidance on my thesis project over the last several years. I also want to thank Dr. Elizabeth Debski for agreeing to be my outside examiner.
I thank my teaching mentor and friend, Dr. Dexter Speck, for giving me so much of his time and expertise in my training. I truly enjoyed my training and practice in teaching physiology and, aside from my research, consider it a true passion in my life.
My development as a scientist was not attributed to my mentors and committee members alone and so I extend my thanks to all of the Smyth and Morris lab members, both past and present, for their patience and support over the years. I wish to extend my gratitude to members of the Cardiovascular Research Department including the Daugherty lab and the Temel lab for their help and training that was essential in the development of my thesis.
I thank all of the friends I have made throughout my time at the University of Kentucky, both in and out of research, for providing me with countless laughs and keeping me both humble and grounded.
Lastly, I would like to thank my family for their support, encouragement, and unending curiosity as to when I would finish my graduate education at the University of Kentucky. To my father Steve, my mother Debbie, and my brothers Bryan and Andy for always providing me with love and laughter.