The Role of the KLF2 in Vascular Endothelial Cells

描述(申请人提供)：这些研究的总体目标是确定血管生物学中内皮细胞KLF2转录因子的机械诱导和功能。我们的实验室进行了大量研究，对了解KLF2做出了重大贡献。包括KLF2基因的原始克隆，缺乏KLF2表达的动物的发育和检测，以及启动流体切应力对内皮细胞KLF2基因调控的研究。KLF2在内皮细胞生物学中发挥着重要作用。体外和体内对人和小鼠血管内皮细胞的实验表明，KLF2在脉动层流切应力下显示出持续的诱导，这是一种公认的具有血管保护特性的生物力学刺激。此外，大量的体外研究表明，KLF2基因的表达有可能降低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。这些研究将扩展我们之前在负责KLF2表达上调的机械转导通路上的工作，以响应液体流动。他们还将率先测试KLF2的表达是否足以降低动脉粥样硬化小鼠模型的病变严重程度。此外，他们将使用条件性基因敲除和转基因过表达的小鼠动物模型，在体内确定KLF2对血管扩张的贡献。重要的是，它们将作为进一步研究KLF2作为血管保护性治疗靶点的先决条件。

DESCRIPTION (provided by applicant): 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.