VEGF, Transcriptional Networks and Vascular Inflammation

VEGF、转录网络和血管炎症

• 批准号: 7211754
• 负责人: William C Aird
• 金额: $ 38.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211754
• 关键词: Adhesions; Animal Model; Animals; Apoptosis; Attenuated; Avastin; Blood Vessels; Cell Adhesion Molecules; Cell physiology; Coagulation Process; Condition; Coupled; DNA-Protein Interaction; Disease; Dominant-Negative Mutation; Electrophoretic Mobility Shift Assay; Endothelial Cells; Endothelium; Foundations; Gene Delivery; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Goals; Harvest; Health; Heart; Hemostatic function; Homeostasis; Human; ICAM1 gene; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Knockout Mice; Lead; Leukocytes; Link; Lung; Malignant Neoplasms; Maps; Mediating; Microvascular Permeability; Mitogens; Modality; Modeling; Mus; Myocardial Ischemia; NADPH Oxidase; NF-AT; NF-kappa B; Pathway interactions; Pattern; Permeability; Phenotype; Play; Property; Research Personnel; Role; Sentinel; Sepsis; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Time; Tissues; Transact; Transcriptional Regulation; Transgenic Organisms; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Wild Type Mouse; Wound Healing; angiogenesis; chromatin immunoprecipitation; in vivo; insight; intraperitoneal; programs; promoter; research study; transcription factor; tumor growth; vascular inflammation

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.

描述（由申请方提供）：血管内皮生长因子（VEGF）是一种内皮细胞（EC）特异性有丝分裂原和趋化剂，参与伤口修复、缺血组织血管生成、肿瘤生长、微血管通透性、血管保护和止血。在过去的几年里，已经有一个主要的推力，开发治疗，要么降低VEGF水平或活性（如阿瓦斯丁在癌症），或增加VEGF（如基因递送策略在缺血性心脏病）。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可以通过转录和/或转录后机制改变EC表型。参与VEGF信号传导的转录因子包括NF-kB、Egr-1、NF-AT和加塔。这项建议的总体目标是确定炎症和凝血中VEGF信号传导的转录机制。第一个目的是探讨VEGF诱导VCAM-1和ICAM-1表达的机制。在第二个目标中，将采用siRNA和显性负性方法来映射VEGF响应性转录因子与靶基因表达/细胞功能之间的联系。第三个目标是致力于健康和疾病中VEGF应答转录网络的体内分析，特别强调败血症。一个更完整的理解的转录机制，VEGF是偶联到内皮细胞表型应该提供一个框架，定制和微调血管疾病状态的治疗方式。