Spatial and Temporal Dynamics of vWF Gene Expression

vWF 基因表达的时空动态

基本信息

批准号：
8001265
负责人：
William C Aird
金额：
$ 48.47万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8001265
关键词：
Agonist Arteries Binding Sites Biological Biology Biomechanics Blood Blood Circulation Blood Vessels Blood capillaries Brain Cells Clinical Code Coronary Artery Bypass Cues DNA Development Disease Down-Regulation Elements Endothelial Cells Endothelium Endotoxemia Endotoxins Epigenetic Process Fistula Foundations Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Health Heart Heterogeneity Human Immune response Infection Instruction Introns Laboratories LacZ Genes Light Mediating Megakaryocytes Messenger RNA Modeling Molecular Mus Organ Pathway interactions Phenotype Program Research Project Grants Proteins Regulation Regulatory Element Regulatory Pathway Relative (related person)Repression Role Sepsis Side Site Skeletal Muscle TNF gene Testing Tissue-Specific Gene Expression Transcriptional Regulation Transgenes Vascular Endothelial Cell Veins Venous Weight Work base capillary extracellular factor A gene repression hemodynamics in vivo insight interest mRNA Expression mouse model novel programs promoter research study transcription factor vascular bed von Willebrand Factor

项目摘要

PROJECT SUMMARY (See instructions): Von Willebrand factor (vWF) is a procoagulant that is expressed specifically in endothelial cells (ECs) and megakaryocytes. Preliminary studies demonstrate several interesting features of vWF gene regulation. First, vWF is preferentially expressed in veins compared with arteries and exposure of cultured ECs to venous flow results in higher expression of vWF expression compared with arterial flow. Second. vWF expression in ECs from different organs is mediated by distinct DNA promoter elements. Third, sepsis is associated with increased circulating levels of vWF protein, yet widespread repression of vWF transcription, an effect that may be explained by reduced transcriptional activity of the ETS factors, ERG. Based upon this background, the overall hypothesis is that vWF expression is spatially and temporally regulated by mechanisms that involve hemodynamic forces, vascular bed/organ-specific transcriptional modules and the ETS factor. Aim 1 will test the hypothesis that arterial-venous differences in vWF expression are mediated by flow. Aim 2 will test the hypothesis that the vWF promoter contains c/s-regulatory elements that direct vascular bed-specific gene expression in the capillaries and veins of heart and skeletal muscle. Aim 3 will test the hypothesis that the repression of vWF in endotoxemia is mediated by ERG activity.

项目摘要（请参阅说明）： von Willebrand因子（VWF）是一种proc仪，在内皮细胞（ECS）和巨核细胞中特别表达。初步研究证明了VWF基因调节的几个有趣特征。首先，与动脉相比，VWF优先在静脉中表达，并且与动脉流相比，培养的ECS暴露于静脉流动导致VWF表达的表达更高。第二。来自不同器官的EC中的VWF表达是由不同的DNA启动子元素介导的。第三，败血症与VWF蛋白的循环水平升高有关，但对VWF转录的广泛抑制作用，这种作用可以通过ETS因子的转录活性降低来解释。基于这种背景，总体假设是VWF表达在空间和时间上受到涉及血液动力学，血管床/器官特异性转录模块和ETS因子的机制的调节。 AIM 1将检验以下假设：VWF表达中的动脉差异是由流动介导的。 AIM 2将检验以下假设：VWF启动子含有C/S调节元件，这些元素可以在心脏和骨骼肌的毛细血管和静脉中引导血管床特异性基因表达。 AIM 3将检验以下假设：内毒素血症中VWF的抑制是由ERG活性介导的。