The Role of the KLF2 in Vascular Endothelial Cells

这些研究的总体目标是确定内皮细胞KLF2的机械诱导和功能 血管生物学中的转录因子。我们的实验室已经进行了大量的研究， 对理解KLF2做出了重大贡献。其中包括KLF2基因的原始克隆，即 缺乏KLF2表达的动物的发育和检测，以及对KLF2表达缺失的研究的启动 流体剪切力对内皮细胞KLF2基因的调控。KLF2在血管内皮细胞中的重要作用 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 在脉动层流剪应力下表现出持续的诱导，这是一种公认的生物力学刺激 VASO-保护性能。此外，大量的体外研究表明，KLF2基因 表达可能降低血管内皮细胞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的内皮表型，因此， 导致KLF2表达的机制代表着重要的治疗靶点。这些研究将扩大 根据我们先前关于导致KLF2上调的机械转导通路的工作 响应流体流动的表达。他们还将率先测试KLF2的表达是否足够 降低小鼠动脉粥样硬化模型的病变严重程度。此外，它们还将定义 KLF2在条件基因敲除和转基因过表达的体内血管扩张中的作用 小鼠动物模型。重要的是，它们将作为进一步调查KLF2作为一种 血管保护性治疗靶点。

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.