VEGF, Transcriptional Networks and Vascular Inflammation

血管内皮生长因子(VEGF)是一种内皮细胞(EC)特异性有丝分裂原，具有趋化作用 它参与伤口修复、缺血组织的血管生成、肿瘤生长、微血管 渗透性、血管保护和止血。在过去的几年里，有一个重大的 致力于开发降低血管内皮生长因子水平或活性的疗法(例如，癌症中的阿瓦斯丁)，或 增加血管内皮生长因子(例如，缺血性心脏病的基因传递策略)。同时，还有 越来越多的证据表明，血管内皮生长因子在调节炎症和凝血方面发挥作用。血管内皮生长因子可能会改变 EC的表型通过转录和/或转录后机制。在抄本中 参与血管内皮细胞生长因子信号转导的因子有：核因子-kB、Egr-1、核因子-AT和GATA。总目标 这项建议的目的是确定炎症中支持血管内皮生长因子信号转导的转录机制 和凝固性。第一个目的是探索血管内皮生长因子诱导血管细胞黏附分子-1和血管细胞黏附分子表达的机制。 ICAM-1。在第二个目标中，将使用siRNA和显性否定方法来定位链接 血管内皮生长因子反应转录因子与靶基因表达/细胞功能之间的关系。第三个目标 致力于健康和疾病中对血管内皮生长因子反应转录网络的体内分析，具有 特别强调败血症。对转录机制有了更全面的了解 血管内皮生长因子与内皮细胞表型的偶联应提供一个剪裁和微调的框架 血管疾病状态下的治疗方式。

Vascular endothelial growth factor (VEGF) is an endothelial cell (EC)-specific mitogen, and chemotactic agent, which is involved in wound repair, angiogenesis of ischemic tissue, tumor growth, microvascular permeability, vascular protection, and hemostasis. Over the past several years, there has been a major thrust towards developing therapies that either decrease VEGF levels or activity (e.g. Avastin in cancer), or increase VEGF (e.g. gene delivery strategies in ischemic heart disease). At the same time, there is increasing evidence that VEGF plays a role in modulating inflammation and coagulation. VEGF may alter EC phenotype through transcriptional and/or post-transcriptional mechanisms. Among the transcription factors that have been implicated in VEGF signaling are NF-kB, Egr-1, NF-AT, and GATA. The overall goal of this proposal is to identify the transcriptional mechanisms that underlie VEGF signaling in inflammation and coagulation. The first aim will explore mechanisms by which VEGF induces expression of VCAM-1 and ICAM-1. In the second aim, siRNA and dominant negative approaches will be employed to map links between VEGF-responsive transcription factors and target gene expression/cellular function. The third aims is dedicated to an in vivo analysis of VEGF-responsive transcriptional networks in health and disease, with a particular emphasis on sepsis. A more complete understanding of the transcriptional mechanisms by which VEGF is coupledto endothelial cell phenotype should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states.