Role of KLF6 in macrophage lipid homeostasis and atherogenesis

KLF6 在巨噬细胞脂质稳态和动脉粥样硬化形成中的作用

• 批准号: 9266485
• 负责人: Ganapati Holanagadde Mahabaleshwar
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266485
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Vessels; Cause of Death; Cells; Cholesterol; Clinical; Clinical Research; Development; Disease Progression; Enzymes; Event; Experimental Models; Exposure to; Family; Foam Cells; Gene Expression; Genes; Genetic Engineering; Genetic Transcription; Healthcare; Homeostasis; Human; Inflammatory; Innate Immune System; Interferon Type II; Interferons; Interleukin-13; Interleukin-4; Knowledge; Kruppel-like transcription factors; Lipid-Laden Macrophage; Lipids; Macrophage Activation; Metabolism; Molecular; Morbidity - disease rate; Myelogenous; Pathogenesis; Pathologic; Production; Public Health; Role; Signal Pathway; Stimulus; Subendothelial Layer; United States; Zinc Fingers; atherogenesis; base; cellular development; chemokine; cytokine; design; experimental study; gene function; health care cost/financing; in vivo; insight; macrophage; member; monocyte; mortality; mouse model; novel therapeutics; oxidized low density lipoprotein; public health relevance; transcription factor; uptake

 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.

 描述（由适用提供）：动脉粥样硬化及其并发症是全球死亡的主要原因。它们还为医疗保健财务燃烧做出了重大贡献，是美国死亡率和发病率的主要主要原因。临床，病理和实验研究支持巨噬细胞在动脉粥样硬化病变发展和发展中的重要作用。动脉粥样硬化斑块发展的标志性事件是在受影响的血管的亚内皮层中含有脂质巨噬细胞衍生的泡沫细胞的积累。尽管公共健康的重要性，但尚不清楚控制巨噬细胞激活及其对动脉粥样硬化发病机理的贡献的分子事件。我们最近将KLF6确定为巨噬细胞炎症基因表达和功能的关键转录调节剂。我们的观察结果表明，（1）KLF6是巨噬细胞中最丰富的Kruppel样转录因子。 （2）暴露于促炎性刺激（例如IFN-γ和OXLDL）后，巨噬细胞中KLF6的表达升高； （3）KLF6促进巨噬细胞中促炎的基因表达； （4）抗炎细胞因子治疗抑制巨噬细胞KLF6表达； （5）源自人动脉粥样硬化病变的巨噬细胞中KLF6的表达升高； （6）KLF6的髓样缺乏减弱巨噬细胞脂质会影响基因表达，脂质积累和泡沫细胞的形成。基于这些观察结果，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的关键调节剂。我们提出以下目的是确定巨噬细胞KLF6在动脉粥样硬化发病机理中的精确作用。在AIM 1中，我们将通过KLF6调节的炎症基因表达来检查精确的分子机制。在AIM 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AIM 3中，我们将研究髓样KLF6在动脉粥样硬化的实验模型中的作用。这些研究结束时，我们将扩大对髓样KLF6对动脉粥样硬化发病机理的贡献的了解。这可以为设计针对治疗动脉粥样硬化的新型疗法提供分子见解。