Forkhead Signaling in the Endothelium

描述(申请人提供)：内皮细胞表型在健康和疾病中表现出显著的异质性。血管生物学的一个重要目标是了解内皮细胞表型时空调控的分子机制。我们最近已经证明：1)叉头转录因子在内皮细胞中有结构性表达，2)血管内皮生长因子、肿瘤坏死因子-α和凝血酶诱导原代人内皮细胞中1个或多个叉头蛋白的磷酸化，3)叉头转录因子的可诱导磷酸化与靶基因表达减少和内皮细胞功能改变相耦合。综上所述，这些数据支持这样的假设，即叉头转录因子在内皮细胞中发挥信号转导的作用，将细胞外环境的短期变化与基因表达的下游变化联系起来。这个项目的总体目标是确定叉头转录因子在内皮细胞内传递细胞外信号中的作用。对这些机制的更完整的理解应该为在血管疾病状态下定制和微调治疗方式提供一个框架。

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.