VEGF, Transcriptional Networks and Vascular Inflammation

描述(申请人提供)：血管内皮生长因子(VEGF)是一种内皮细胞(EC)特异性的有丝分裂原和趋化因子，参与伤口修复、缺血组织的血管生成、肿瘤生长、微血管通透性、血管保护和止血。在过去的几年里，人们一直在大力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的疗法(例如，缺血性心脏病的基因传递策略)。与此同时，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通过转录和/或转录后机制改变EC的表型。参与血管内皮细胞生长因子信号转导的转录因子包括核因子-kB、Egr-1、核因子-AT和GATA。这项建议的总体目标是确定炎症和凝血过程中支持血管内皮生长因子信号的转录机制。第一个目的是探讨血管内皮细胞生长因子诱导血管细胞黏附分子-1和细胞间黏附分子-1表达的机制。在第二个目标中，将使用siRNA和显性负性方法来定位血管内皮生长因子反应转录因子和靶基因表达/细胞功能之间的联系。第三个目标是致力于体内分析血管内皮生长因子在健康和疾病中的转录反应网络，特别强调败血症。对血管内皮生长因子与血管内皮细胞表型的转录机制有了更全面的了解，将为血管疾病状态下的治疗提供一个框架。

DESCRIPTION (provided by applicant): 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 aim 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 coupled to endothelial cell phenotype should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states.