Von Willebrand factor (vWF) is a procoagulant that is expressed specifically in endothelial cells (ECs) and megakaryocytes. Preliminary studies demonstrate several interesting features of vWF gene regulation. First, vWF is preferentially expressed in veins compared with arteries and exposure of cultured ECs to venous flow results in higher expression of vWF expression compared with arterial flow. Second. vWF expression in ECs from different organs is mediated by distinct DNA promoter elements. Third, sepsis is associated with increased circulating levels of vWF protein, yet widespread repression of vWF transcription, an effect that may be explained by reduced transcriptional activity of the ETS factors, ERG. Based upon this background, the overall hypothesis is that vWF expression is spatially and temporally regulated by mechanisms that involve hemodynamic forces, vascular bed/organ-specific transcriptional modules and the ETS factor.
Aim 1 will test the hypothesis that arterial-venous differences in vWF expression are mediated by flow.
Aim 2 will test the hypothesis that the vWF promoter contains c/s-regulatory elements that direct vascular bed-specific gene expression in the capillaries and veins of heart and skeletal muscle.
Aim 3 will test the hypothesis that the repression of vWF in endotoxemia is mediated by ERG activity.
The overall significance of these studies is that they will provide new insights into mechanisms of EC heterogeneity and lay a foundation for vascular bed-specific targeting. Experiments in Aim 1 are significant because they will provide new insights into the plasticity of the endothelium and the role of flow in mediating differential gene expression. Studies in Aim 2 are significant in that they will extend our observations related to the modular regulation of vWF expression. Finally, Aim 3 will yield important information about spatial and temporal regulation of EC gene expression in sepsis, which is a prevalent pathophysiological condition in humans.
|Yuan, Lei; Chan, Gary C; Beeler, David et al. (2016) A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity. Nat Commun 7:10160|
|Bai, Aiping; Robson, Simon (2015) Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161. Purinergic Signal 11:317-9|
|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, A; Kokkotou, E; Zheng, Y et al. (2015) Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses. Cell Death Dis 6:e1828|
|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|
|Bai, Aiping; Moss, Alan; Kokkotou, Efi et al. (2014) CD39 and CD161 modulate Th17 responses in Crohn's disease. J Immunol 193:3366-77|
|Aird, William C; Mosnier, Laurent O; Fairhurst, Rick M (2014) Plasmodium falciparum picks (on) EPCR. Blood 123:163-7|
|Rowe, Glenn C; Raghuram, Srilatha; Jang, Cholsoon et al. (2014) PGC-1Î± induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115:504-17|
|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|
|Bian, Shu; Sun, Xiaofeng; Bai, Aiping et al. (2013) P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One 8:e60184|
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