The role of immunometabolic pathways in atherosclerosis

描述（由申请人提供）：动脉粥样硬化和相关心血管疾病（CVD）是美国发病率和死亡率的主要原因。动脉粥样硬化以动脉壁脂质积累为特征，是一种炎症性疾病，包括巨噬细胞在内的几种免疫效应物在其中起核心作用。肥胖、胰岛素抵抗、糖尿病和血脂异常都是心血管疾病的主要危险因素，但代谢紊乱与炎症和动脉粥样硬化发展之间的联系机制仍有待阐明。我们发表的工作和初步数据表明，双链RNA激活的蛋白激酶PKR在肥胖的背景下被激活，它在驱动炎症和葡萄糖稳态恶化中起着关键作用。在巨噬细胞中，暴露于脂毒性信号和脂蛋白激活PKR。此外，PKR是激活NLRP3炎性体和应激信号通路（如JNK）的关键成分，这些信号通路与糖尿病和动脉粥样硬化的发病机制有关。此外，在本提案中提供的支持数据中，我们证明了对pkr缺陷小鼠动脉粥样硬化斑块发展的显着保护。基于这些发现，我们的首要假设是，通过调节炎症活性、胰岛素作用和蛋白质合成，PKR将细胞应激和代谢信号与慢性炎症和动脉粥样硬化联系起来。本提案中描述的实验将通过确定PKR在巨噬细胞的激活和功能中的作用，以及通过评估体内动脉粥样硬化发展中PKR的全身和巨噬细胞特异性需求来验证这一假设。这一贡献将扩大我们对营养压力与心脏代谢疾病发展之间联系的理解。这项工作的创新之处在于通过确定血脂异常和免疫细胞炎症激活之间的机制联系来研究动脉粥样硬化治疗的新方法。

DESCRIPTION (provided by applicant): Atherosclerosis and associated cardiovascular disease (CVD) are the leading cause of morbidity and mortality in the US. Atherosclerosis is characterized by the accumulation of lipids in the artery wall, and is an inflammatory disease in which several immune effectors including macrophages play a central role. Obesity, insulin resistance, diabetes, and dyslipidemia are all major risk factors for CVD, but the mechanisms that link disordered metabolism to inflammation and the development of atherosclerosis remain to be elucidated. Our published work and preliminary data demonstrate that the double stranded RNA activated protein kinase, PKR, is activated in the context of obesity, where it plays a critica role in driving inflammation and the deterioration of glucose homeostasis. In macrophages, exposure to lipotoxic signals and lipoproteins activate PKR. In addition, PKR is a critical component for the activation of the NLRP3 inflammasome, and stress signaling pathways such as JNK, which are implicated in the pathogenesis of both diabetes and atherosclerosis. In addition, in supporting data presented in this proposal we demonstrate a significant protection against atherosclerotic plaque development in PKR-deficient mice. Based on these findings our overarching hypothesis is that by modulating inflammatory activity, insulin action, and protein synthesis, PKR links cellular stress and metabolic signals to chronic inflammation and atherosclerosis. The experiments described in this proposal will test that hypothesis by determining the role of PKR in the activation and function of macrophages, and by assessing the whole body and macrophage-specific requirement for PKR in the development of atherosclerosis in vivo. This contribution will expand our understanding of the link between nutrient stress and the development of cardiometabolic disease. The innovation of this work lies in investigating a novel approach to atherosclerosis therapy by identifying the mechanistic link between dyslipidemia and inflammatory activation of immune cells.