Role of KLF6 in macrophage lipid homeostasis and atherogenesis

 描述(申请人提供)：动脉粥样硬化及其并发症是全球主要的死亡原因。它们还极大地增加了卫生保健的财政负担，是美国死亡率和发病率的主要原因。临床、病理和实验研究支持巨噬细胞在动脉粥样硬化病变的发生发展中发挥重要作用。动脉粥样硬化斑块发展的一个标志性事件是载脂巨噬细胞来源的泡沫细胞在病变血管的内皮下层积聚。尽管巨噬细胞对公众健康具有重要意义，但其调控巨噬细胞活化的分子事件及其在动脉粥样硬化发病机制中的作用尚不清楚。我们最近发现KLF6是巨噬细胞炎症基因表达和功能的关键转录调节因子。我们的观察结果表明，(1)KLF6是巨噬细胞中表达最丰富的Kruppel样转录因子；(2)KLF6在巨噬细胞中的表达上调；(3)KLF6促进巨噬细胞的促炎基因表达；(4)抗炎细胞因子治疗抑制巨噬细胞的KLF6表达；(5)KLF6在人动脉粥样硬化病变来源的巨噬细胞中表达上调；(6)KLF6髓系缺陷抑制巨噬细胞脂质内流基因的表达，抑制脂肪堆积和泡沫细胞的形成。基于这些观察，我们假设KLF6是巨噬细胞促炎激活、脂质稳态、泡沫细胞形成和动脉粥样硬化形成的关键调节因子。我们提出以下目的，以确定巨噬细胞KLF6在动脉粥样硬化发病机制中的确切作用。目的1，我们将探讨KLF6调控炎症基因表达的确切分子机制。在目标2中，我们将确定KLF6在巨噬细胞脂质稳态和泡沫细胞形成中的作用。在目标3中，我们将研究髓系KLF6在实验性动脉粥样硬化模型中的作用。在这些研究的结论中，我们将扩大我们对髓系KLF6在动脉粥样硬化发病机制中的作用的了解。这可能为设计针对动脉粥样硬化治疗的新疗法提供分子洞察力。

 DESCRIPTION (provided by applicant): Atherosclerosis and its complications are the leading cause of deaths worldwide. They also significantly contribute to the health care financial burden and are the major leading causes of mortality and morbidity in the United States. Clinical, pathological and experimental studies support an important role for macrophages in the development and progression of atherosclerotic lesions. A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophage derived foam cells in the sub endothelial layers of affected blood vessels. Despite its public health importance, the molecular events that govern macrophage activation and its contribution to the pathogenesis of atherosclerosis are not well understood. We have recently identified KLF6 as a critical transcriptional regulator of macrophage inflammatory gene expression and function. Our observations indicated that, (1) KLF6 is the most abundantly expressed Kruppel-like transcription factor in macrophages; (2) KLF6 expression is elevated in macrophages following exposure to pro-inflammatory stimuli such as IFN-γ and oxLDL; (3) KLF6 promotes pro-inflammatory gene expression in macrophages; (4) treatment with anti-inflammatory cytokines suppress macrophage KLF6 expression; (5) KLF6 expression is elevated in macrophages derived from human atherosclerotic lesions; (6) Myeloid deficiency of KLF6 attenuated macrophage lipid influx gene expression, lipid accumulation and foam cell formation. Based on these observations, we hypothesize that KLF6 is a critical regulator of macrophage pro-inflammatory activation, lipid homeostasis, foam cell formation and atherogenesis. We propose following aims to determine the precise role of macrophage KLF6 in pathogenesis of atherosclerosis. In Aim 1, we will examine the precise molecular mechanism by KLF6 regulate inflammatory gene expression. In Aim 2, we will determine the role of KLF6 in macrophage lipid homeostasis and foam cell formation. In Aim 3, we will investigate the role of myeloid KLF6 in experimental models of atherosclerosis. At the conclusion of these studies, we will have expanded our knowledge of myeloid KLF6 contribution to the pathogenesis of atherosclerosis. This may provide the molecular insight to design novel therapies directed at the treatment of atherosclerosis.