Vascular diseases are among the most common causes of morbidity and mortality in the Western world. A remarkable feature of these disorders is the local nature of their distribution;virtually all diseases are associated with focal pathological lesions in characteristic sites of the vascular tree. A key to understanding the mechanisms of focal vasculopathy is found within the endothelium. Endothelial cell (EC) phenotypes are differentially regulated in space and time. Phenotypic heterogeneity is governed largely at the level of gene expression. The integrating theme of this program is that cis-trans and epigenetics contribute to lineage determination and EC heterogeneity. The overall goal is to apply multidisciplinary approaches, including cutting-edge epigenetic assays, gene targeting, embryoid body differentiation assays, flow models and sepsis models to dissect the relative contribution of cis-trans and epigenetic forces in mediating lineage- and vascular bed-specific endothelial gene expression and phenotypes. The PPG integrates investigators with diverse expertise required to advance our understanding of gene regulation in the endothelium. Project 1 (""""""""Spatial and temporal dynamics of von Willebrand factor (vWF) gene expression"""""""";William C. Aird, Project Leader) focuses on molecular mechanisms governing vWF expression in health and disease. Project 2 (""""""""Transcriptional regulation of endothelial differentiation by ERG"""""""";Peter Oettgen, Project Leader) explores the role of the ETS transcription factor ERG in the regulation of EC differentiation, vascular development, and human endothelial progenitor cell function. Project 3 (""""""""Endothelial lineage diversity: role of epigenetics"""""""";Philip Marsden, Project Leader) examines the role of epigenetic forces in mediating endothelial cell-specific gene expression of eNOS. Core A (""""""""Administrative Support"""""""";William C. Aird, Core Leader) provides standard administrative support, including the coordination of all applicable statutory compliance, for the Program. Core B (""""""""Epigenetics Core"""""""";John Whetstine, Core Leader) provides expertise and technical support for studying epigenetic modification of endothelial genes. Core C (""""""""Gene Targeting Core"""""""";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076540-07
Application #
8118166
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
2004-07-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$2,076,535
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Bai, Aiping; Moss, Alan; Rothweiler, Sonja et al. (2015) NADH oxidase-dependent CD39 expression by CD8(+) T cells modulates interferon gamma responses via generation of adenosine. Nat Commun 6:8819
Bai, Aiping; Robson, Simon (2015) Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161. Purinergic Signal 11:317-9
Yan, Matthew S; Marsden, Philip A (2015) Epigenetics in the Vascular Endothelium: Looking From a Different Perspective in the Epigenomics Era. Arterioscler Thromb Vasc Biol 35:2297-306
Okada, Yoshiaki; Funahashi, Nobuaki; Tanaka, Toru et al. (2014) Endothelial cell-specific expression of roundabout 4 is regulated by differential DNA methylation of the proximal promoter. Arterioscler Thromb Vasc Biol 34:1531-8
Turgeon, Paul J; Sukumar, Aravin N; Marsden, Philip A (2014) Epigenetics of Cardiovascular Disease - A New ""Beat"" in Coronary Artery Disease. Med Epigenet 2:37-52
Bai, Aiping; Moss, Alan; Kokkotou, Efi et al. (2014) CD39 and CD161 modulate Th17 responses in Crohn's disease. J Immunol 193:3366-77
Rowe, Glenn C; Raghuram, Srilatha; Jang, Cholsoon et al. (2014) PGC-1? induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115:504-17
Aird, William C; Mosnier, Laurent O; Fairhurst, Rick M (2014) Plasmodium falciparum picks (on) EPCR. Blood 123:163-7

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