Forkhead Signaling in the Endothelium

描述（由申请人提供）：内皮细胞表型在健康和疾病中显示出显著的异质性。血管生物学的一个重要目标是了解内皮细胞表型时空调节的分子机制。我们最近证明：1)叉头转录因子在内皮细胞中组成性表达，2)VEGF、TNF-a和凝血酶诱导原代人内皮细胞中1种或多种叉头蛋白的磷酸化，3)叉头转录因子的诱导磷酸化与靶基因表达的减少和内皮细胞功能的改变相关联。综上所述，这些数据支持叉头转录因子在内皮中作为信号转导器的假设，将细胞外环境的短期变化与下游基因表达的变化耦合在一起。该项目的总体目标是表征叉头转录因子在内皮细胞外信号转导中的作用。对这些机制的更全面的了解应该为血管疾病状态的剪裁和微调治疗模式提供一个框架。

DESCRIPTION (provided by applicant): Endothelial cell 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 endothelial cell phenotypes. We have recently demonstrated that: 1) forkhead transcription factors are constitutively expressed in endothelial cells, 2) VEGF, TNF-a and thrombin induce the phosphorylation of 1 or more of the forkhead proteins in primary human endothelial cells, and 3) the inducible phosphorylation of forkhead transcription factors is coupled to a reduction in target gene expression and alteration in endothelial cell function. Taken together, this data supports the hypothesis that forkhead transcription factors function as signal transducers in the endothelium, coupling short-term changes in the extracellular environment to downstream changes in gene expression. The overall goal of this project is to characterize the role for forkhead transcription factors in transducing extracellular signals within the endothelium. A more complete understanding of these mechanisms should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states.