The Role of the KLF2 in Vascular Endothelial Cells

KLF2 在血管内皮细胞中的作用

基本信息

批准号：
7341585
负责人：
JERRY B LINGREL
金额：
$ 39万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/7341585
关键词：
Ablation Affinity Chromatography Animal Model Animals Aorta Area Atherosclerosis Binding Biological Assay Biology Biomechanics Blood Pressure Blood Vessels Breeding Cellular biology Cloning Condition Coronary heart disease Coupled DNA Development Electrophoretic Mobility Shift Assay Elements Endothelial Cells Endothelium Exhibits Face Fibrinogen Gene Expression Gene Expression Regulation Genes Genetic Polymorphism Goals Health Human In Vitro Integrins Investigation Knock-out Knockout Mice Kruppel-like transcription factors Laboratories Lesion Light Liquid substance Lung Mass Spectrum Analysis Measurement Measures Mediating Methods Modeling Molecular Mus Nature Nuclear Pathway interactions Pattern Phenotype Physiological Play Predisposition Procedures Production Property Regulation Relaxation Role Serological Severities Signal Transduction Pathway Site Small Interfering RNA Stimulus Telemetry Testing Transgenic Mice Transgenic Organisms Up-Regulation Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Vasodilation Work athero susceptible biological adaptation to stress chromatin immunoprecipitation defined contribution fluid flow genetic risk factor in vivo knockout animal mouse model novel therapeutics promoter research study response shear stress therapeutic target transcription factor

项目摘要

The overall goal of these studies is to define the mechano-induction and function of the endothelial KLF2 transcription factor in vascular biology. Our laboratory has performed numerous studies that have contributed significantly to understanding KLF2. These include the original cloning of the KLF2 gene, the development and examination of animals lacking KLF2 expression, and the initiation of studies on the regulation of the endothelial KLF2 gene by fluid shear stress. KLF2 plays an important role in endothelial cell (EC) biology. In vitro and in vivo experiments with human and mouse vascular ECs indicate that KLF2 exhibits sustained induction under pulsatile laminar shear stress, a biomechanical stimulus with recognized vaso-protective properties. Furthermore, numerous in vitro studies have demonstrated that KLF2 gene expression has the potential to reduce the susceptibility of the endothelium to atherosclerosis. We hypothesize that KLF2 mediates athero-protective endothelial phenotypes and, as such, that the mechanisms leading to KLF2 expression represent important therapeutic targets. These studies will expand upon our previous work on the mechano-transduction pathways responsible for the upregulation of KLF2 expression in response to fluid flow. They will also be the first to test whether KLF2 expression is sufficient to decrease the severity of lesions in murine models of atherosclerosis. Additionally, they will define the contribution of KLF2 to vasodilation in vivo using conditional knockout and transgenic over-expressing murine animal models. Importantly, they will serve as a prerequisite for further investigation of KLF2 as a vaso-protective therapeutic target.

这些研究的总体目标是确定内皮 KLF2 的机械诱导和功能血管生物学中的转录因子。我们的实验室进行了大量的研究对理解 KLF2 做出了重大贡献。其中包括 KLF2 基因的原始克隆，缺乏 KLF2 表达的动物的发育和检查，以及关于 KLF2 表达的研究的启动流体剪切应力对内皮 KLF2 基因的调节。 KLF2在内皮细胞中发挥重要作用细胞（EC）生物学。人和小鼠血管内皮细胞的体外和体内实验表明，KLF2 在脉动层流剪切应力下表现出持续诱导，这是一种公认的生物力学刺激血管保护特性。此外，大量体外研究表明KLF2基因表达有可能降低内皮对动脉粥样硬化的易感性。我们假设 KLF2 介导动脉粥样硬化保护性内皮表型，因此，导致 KLF2 表达的机制代表了重要的治疗靶点。这些研究将扩大基于我们之前对负责 KLF2 上调的机械传导途径的研究表达对流体流动的响应。他们也将第一个测试KLF2表达是否足够降低动脉粥样硬化小鼠模型中病变的严重程度。此外，他们将定义使用条件敲除和转基因过表达KLF2对体内血管舒张的贡献小鼠动物模型。重要的是，它们将作为进一步调查 KLF2 作为一个先决条件血管保护治疗目标。