Forkhead Signaling in the Endothelium

描述（由申请方提供）：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的时空调节的分子机制。我们最近已经证明：1）叉头转录因子在内皮细胞中组成型表达，2）VEGF、TNF-α和凝血酶诱导原代人内皮细胞中一种或多种叉头蛋白的磷酸化，和3）叉头转录因子的可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。两者合计，这些数据支持的假设，叉头转录因子的功能作为信号转导在内皮细胞，耦合短期的细胞外环境的变化，下游的基因表达的变化。本项目的总体目标是描述叉头转录因子在内皮细胞内转导细胞外信号中的作用。对这些机制的更全面的理解应该为血管疾病状态下的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.