Endothelial cell (EC) phenotypes display remarkable heterogeneity in health and disease. An important goal in vascular biology is to understand the molecular mechanisms underlying the spatial and temporal modulation of EC phenotypes. This competing renewal application is an extension of our previous work aimed towards elucidating the role of forkhead (FOXO) transcription factors in EC biology. Three novel and exciting aspects of FOXO biology have emerged in the past 3 years, which together with our own published data and preliminary results provide a strong foundation for the current proposal: 1) despite the fact that FOXO proteins are ubiquitously expressed, FOXO- deficient mice display a vascular phenotype, whether the gene is deleted during embryogenesis or in adults, 2) the vascular phenotype is organ-specific and FOXO-deficient ECs from different organs demonstrate different gene expression patterns and functional changes, and 3) FOXO proteins (at least in other cell types) have been shown to bind to and/or interact with a broad spectrum of transcription factors. Based on these considerations, we hypothesize that FOXO proteins (in particular FOXO1) cooperate with other transcription factors to regulate EC phenotypes. The overall goal is to identify FOXO1-associated transcriptional networks in ECs, to understand how these mediate vascular bed-specific gene expression, and to define the in vivo role of FOXO1 in the intact endothelium.
Aim 1 is to characterize functional interactions between FOXO1 and other transcription factors in ECs.
Aim 2 is to characterize combinatorial gene regulation by FOXO1 and NF-kB in ECs.
Aim 3 is to analyze the effect of conditional FOXO1 over-expression and knockout on EC function and dysfunction in normal and pathological states.
The proposal is significant in that it will provide important insights into the mechanisms (hence therapeutic potential) of FOXO1-mediated EC signal transduction.
|Dharaneeswaran, Harita; Abid, Md Ruhul; Yuan, Lei et al. (2014) FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis. Circ Res 115:238-51|
|Bentley, Katie; Philippides, Andrew; Ravasz Regan, ErzsÃ©bet (2014) Do endothelial cells dream of eclectic shape? Dev Cell 29:146-58|
|Filipovic, Nenad; Gibney, Barry C; Nikolic, Dalibor et al. (2014) Computational analysis of lung deformation after murine pneumonectomy. [corrected]. Comput Methods Biomech Biomed Engin 17:838-44|
|Lee, Monica; Spokes, Katherine C; Aird, William C et al. (2010) Intracellular Ca2+ can compensate for the lack of NADPH oxidase-derived ROS in endothelial cells. FEBS Lett 584:3131-6|
|Shapiro, Nathan I; Yano, Kiichiro; Sorasaki, Midori et al. (2009) Skin biopsies demonstrate site-specific endothelial activation in mouse models of sepsis. J Vasc Res 46:495-502|
|Ganopolsky, J G; Abid, Md R; Aird, W C et al. (2008) GAS6-induced signaling in human endothelial cells is mediated by FOXO1a. J Thromb Haemost 6:1804-11|
|Abid, Md Ruhul; Nadeau, Robert J; Spokes, Katherine C et al. (2008) Hepatocyte growth factor inhibits VEGF-forkhead-dependent gene expression in endothelial cells. Arterioscler Thromb Vasc Biol 28:2042-8|
|Yano, Kiichiro; Okada, Yoshiaki; Beldi, Guido et al. (2008) Elevated levels of placental growth factor represent an adaptive host response in sepsis. J Exp Med 205:2623-31|
|Abid, Md Ruhul; Spokes, Katherine C; Shih, Shou-Ching et al. (2007) NADPH oxidase activity selectively modulates vascular endothelial growth factor signaling pathways. J Biol Chem 282:35373-85|
|Yano, Kiichiro; Liaw, Patricia C; Mullington, Janet M et al. (2006) Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med 203:1447-58|
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