VEGF, Transcriptional Networks and Vascular Inflammation

血管内皮生长因子（VEGF）是内皮细胞（EC）特异性的有丝分裂原和趋化因子， 试剂，其参与伤口修复、缺血组织的血管生成、肿瘤生长、微血管生成、血管生成 渗透性、血管保护和止血。在过去的几年里，有一个主要的 致力于开发降低VEGF水平或活性的疗法（例如，癌症中的Avastin），或 增加VEGF（例如缺血性心脏病中的基因递送策略）。与此同时， 越来越多的证据表明VEGF在调节炎症和凝血中起作用。VEGF可能会改变 EC表型通过转录和/或转录后机制。其中转录 参与VEGF信号传导的因子是NF-κ B、Egr-1、NF-AT和加塔。总目标 这项提议的一个目的是确定炎症中VEGF信号传导的转录机制 和凝固。第一个目标是探索VEGF诱导VCAM-1表达的机制， ICAM-1。在第二个目标中，将采用siRNA和显性阴性方法来绘制链接 VEGF应答性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VEGF应答转录网络的体内分析， 尤其是败血症更完整地理解转录机制， VEGF与内皮细胞表型的结合应该为定制和微调提供一个框架 血管疾病状态的治疗方式。

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.