Postdoctoral Fellow (Cardiovascular Pathophysiology, Genomics), 2001-2005, University of Pennsylvania
Ph.D. in Biomedical Engineering, 2001, The University of Akron
M.S. in Biomedical Engineering, 1996, The University of Akron
B.S. in Chemical Engineering, 1994, The University of Akron
Biomedical Engineering Graduate Group
Temporal and spatial responses of vascular endothelial cells (EC) to molecular and mechanical stimuli result in phenotypic heterogeneity that influences normal physiology and various pathologies. Atherosclerosis, a chronic inflammatory disease of arteries and an underlying cause of heart attack, stroke and peripheral arterial disease, remains a major cause of morbidity and mortality in the western world. There is a strong correlation between local flow characteristics and focal susceptibility to atherosclerosis, suggesting that regional arterial hemodynamics is an important determinant of EC phenotype.
A major focus of my research is the characterization of regional endothelial phenotypic heterogeneity from a standpoint of susceptibility to atherosclerotic disease. The current emphasis is on the evaluation of differential steady-state gene expression profiles as a function of hemodynamics in arteries. One major goal is to identify a minimal set of common features (associated with clinically relevant areas) that define a “fingerprint” or “signature” for susceptibility to atherosclerosis.
EC phenotypic heterogeneity then is the context in which to evaluate the relative contributions of intrinsic and environmental risk factors to disease. For example, metabolic syndrome (a clustering of risk factors including hypercholesterolemia, insulin resistance, etc.) is associated with an increased risk of cardiovascular disease and present in a large proportion of the adult population. A second focus of my research is the characterization of phenotypic and functional changes in vascular EC introduced by cardiovascular risk factors. One primary goal is to identify a set of novel biomarkers that correlate with increased susceptibility to disease and can be used as prognostic / diagnostic tools for physicians.
Pharmacological intervention (e.g. with statins) is commonly used in combination with lifestyle changes to treat cardiovascular risk factors. Intervention to treat occlusive atherosclerotic disease involves surgical procedures such as arterial bypass grafting and balloon angioplasty with stenting. The placement of devices such as vascular grafts and stents can result not only in a wound healing response, but also in altered geometries and local flow characteristics. This results in remodeling of the vessel wall and failure modes such as intimal hyperplasia and restenosis which involve the mechanically-responsive endothelium. A third focus for my research is the evaluation of therapeutic interventions and device failure in the context of endothelial phenotypic heterogeneity.
In order to accomplish these goals we will utilize state-of-the-art technologies in genomics, proteomics and computational biology in my laboratory and within the Genome Center (including laser capture microdissection, microarrays, real-time PCR, mass spectrometry, immunohistochemistry and confocal microscopy). In vitro studies will be pursued in parallel with in vivo experiments to enhance our understanding of biological mechanisms. The nature of our work will be highly interdisciplinary and hypothesis-driven. Ultimately, the goal is to provide insight into disease mechanisms and to help guide the development of novel strategies for prevention, diagnosis and intervention.
Major Research Interest
Cardiovascular genomics; pathology of atherosclerosis; vascular hemodynamics; endothelial cell mechanotransduction; vascular device intervention and failure; genomics, proteomics and high-throughput screening technologies; biomarker identification for diagnostic/ therapeutic application; bioinformatics approaches.
Passerini AG, Shi C, Francesco NM, Chuan P, Manduchi E, Grant GR, Stoeckert CJ Jr., Karanian JW, Wray-Cahen D, Pritchard WF, Davies PF. (2005) Regional determinants of arterial endothelial phenotype dominate the impact of gender or short-term exposure to a high-fat diet. Biochem. Biophys. Res. Commun. 332: 142-148.
Davies PF, Passerini AG, Simmons CA. (2004) Aortic valve: turning over a new leaf(let) in endothelial phenotypic heterogeneity. Arterioscler. Thromb. Vasc. Biol. 24 (8): 1331-1333.
Passerini AG, Polacek DC, Shi C, Francesco NM, Manduchi E, Grant GR, Pritchard WF, Powell S, Chang GY, Stoeckert CJ Jr., Davies PF. (2004) Coexisting pro-inflammatory and anti-oxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc. Natl. Acad. Sci. USA 101(8): 2482-2487.
Polacek DC*, Passerini AG*, Shi C, Francesco NM, Manduchi E, Grant GR, Powell S, Bischof H, Winkler H, Stoeckert CJ Jr., Davies PF. (2003) Fidelity and enhanced sensitivity of differential transcription profiles following linear amplification of nanogram amounts of endothelial mRNA. Physiol. Genomics 13: 147-156. (* shared first authorship)
Passerini AG, Milsted A, Rittgers SE. (2003) Shear stress magnitude and directionality modulate growth factor gene expression in preconditioned vascular endothelial cells. J. Vasc. Surg. 37: 182-190.