This highly integrated program is focused on the study of factors influencing discrete regional susceptibility to atherogenesis. The complex interplay of mechanical forces and chemical mediators which impinge on platelet vascular interactions and on cells of the vessel wall and their interaction with the extracellular matrix will be elucidated. Distinct and overlapping signaling pathways will be integrated by genomic and proteomic interrogation of determinants of the balance between susceptibility to and protection from atherosclerosis. Particular attention will be paid to how traditional risk factors, including age, hyperiipidemia and gender condition cell signaling pathways of relevance to inflammation and the cell cycle. In Project 1 the role of COX-2 and mPGES-1, will be assessed. Novel mouse models will delineate their contribution in endothelial, vascular smooth muscle cells, macrophages and cardiomyocytes to cardiovascular function. A priori hypothesis testing will complement unbiased approaches to assess the impact of enzyme disruption on discrete phenotypes and biological networks. In Project 4 the interaction between the ApoE/COX-2/PGl2/IP pathway and the cell cycle will be probed, using cell specific deletions and forced expression of COX-2, deletion, antagonism and stimulation of the IP and by using biophysical approaches to assess differential impact on the extracellular matrix. Finally, in Project 5 we shall examine the effect of gender and hyperiipidemia on the discrete expression of genomic subsets in endothelial cells obtained from regions of the pig aorta susceptible to and protected from atherogenesis. This program will take an integrated approach to the study of humoral and mechanical signaling in vascular cells. Factors that underlie the cell to cell heterogeneity of this interaction are likely to contribute to the focal nature of atherogenesis.

Public Health Relevance

Cardiovascular disease continues to be the leading cause of death in the United States. Burgeoning incidence of metabolic syndrome, in both the developed and developing world, suggests that this challenge to public health will grow. Our work will pursue new approaches to understanding atherogenesis, the developmental process of atheromatous plaques, using complex approaches to structural biology, genomics, proteomics and metabolomics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062250-15
Application #
8492128
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
1999-04-07
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$2,158,552
Indirect Cost
$720,370
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tang, Soon Yew; Monslow, James; R Grant, Gregory et al. (2016) Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1-Deficient Hyperlipidemic Mice. Circulation 134:328-38
Jiang, Yi-Zhou; Manduchi, Elisabetta; Stoeckert Jr, Christian J et al. (2015) Arterial endothelial methylome: differential DNA methylation in athero-susceptible disturbed flow regions in vivo. BMC Genomics 16:506
Liu, Shu-Lin; Bae, Yong Ho; Yu, Christopher et al. (2015) Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. Sci Rep 5:17189
Han, Jingyan; Shuvaev, Vladimir V; Davies, Peter F et al. (2015) Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1. J Control Release 210:39-47
Jiang, Yi-Zhou; Manduchi, Elisabetta; Jiménez, Juan M et al. (2015) Endothelial epigenetics in biomechanical stress: disturbed flow-mediated epigenomic plasticity in vivo and in vitro. Arterioscler Thromb Vasc Biol 35:1317-26
Sweet, Daniel T; Jiménez, Juan M; Chang, Jeremy et al. (2015) Lymph flow regulates collecting lymphatic vessel maturation in vivo. J Clin Invest 125:2995-3007
Hsu, Bernadette Y; Bae, Yong Ho; Mui, Keeley L et al. (2015) Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2. PLoS One 10:e0128974
Tang, Soon Yew; Monslow, James; Todd, Leslie et al. (2014) Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice. Circulation 129:1761-9
Jiménez, Juan M; Prasad, Varesh; Yu, Michael D et al. (2014) Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression. J R Soc Interface 11:20131079
Jiang, Yi-Zhou; Jiménez, Juan M; Ou, Kristy et al. (2014) Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. Circ Res 115:32-43

Showing the most recent 10 out of 157 publications