Macrophage-specific IEX-1 – A Novel Mechanism in the Pathogenesis of Atherosclerosis

巨噬细胞特异性 IEX-1 — 动脉粥样硬化发病机制的新机制

• 批准号: 10112269
• 负责人: Mohd Shahid
• 金额: $ 11.1万
• 依托单位: CHICAGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112269
• 关键词: Address; Aorta; Aortitis; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Cell Lineage; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; Cre-LoxP; Data; Development; Diabetes Mellitus; Diagnostic; Disease; ERG gene; Enterobacteria phage P1 Cre recombinase; Exhibits; Foam Cells; Gene Expression; Genes; Genetic Recombination; Glycolysis; Human; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Ingestion; Investigation; Lipids; Mediating; Molecular; Morbidity - disease rate; Muramidase; Mus; Myeloid Cells; Myocardial Ischemia; Obesity; Partner in relationship; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Play; Production; Regulation; Research Proposals; Resistance; Role; Stress; Stroke; Therapeutic; atherogenesis; attenuation; base; cell type; chronic inflammatory disease; effective therapy; insight; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; polarized cell; prevent; promoter; recruit

Macrophage-specific IEX-1 – A Novel Mechanism in the Pathogenesis of Atherosclerosis Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the artery wall. It is the leading cause of morbidity and mortality in the US. Several immune cells are involved in genesis of atherosclerosis; however, macrophages play a central role in all stages of the disease. Emerging evidence suggests that both the quantity and phenotype of macrophages influence the inception and progression of atherosclerotic lesions. Several macrophages subsets have been identified in atherosclerotic plaques, including classically-activated (CAMs), alternatively-activated (AAMs), and Mox based on their distinct gene expression. Macrophages with CAMs-like characteristics play a crucial role in initiation of atherosclerosis by infiltrating in sub-endothelial space and promoting inflammation. They engulf lipids and become foam cell to form plaque. In contrast, AAMs-like macrophages are enriched in regressing plaques. They inhibit inflammation and exhibit reduced foam cell formation. However, the identity of bona fide factors that critically regulate macrophage phenotype remain poorly understood. As a result, there is a dearth of the effective strategies to inhibit pro-atherogenic phenotype of macrophages to reduce atherosclerosis. IEX-1 is a stress- inducible gene that is highly expressed in macrophages. Our preliminary investigation revealed that IEX-1 is essential for atherosclerosis development and that its deficiency protected mice against atherosclerosis without impacting cholesterol metabolism. Interestingly, IEX-1 deficiency reversed the phenotype of macrophages infiltrated in aorta from CAMs to a AAMs-like state, with only little effect on macrophage infiltration. AAMs- biased polarization preceded the development of atherosclerotic plaque. In the current proposal we will address the hypothesis that IEX-1 activity in macrophages is required for atherogenesis. To address this, we propose to use a novel mouse model in which IEX-1 will be selectively deleted from macrophages on ApoE- deficiency background. We will study its impact on atherosclerotic plaque formation, aortic macrophage phenotype, and inflammatory status. Furthermore, to gain a mechanistic insight into how IEX-1 contributes to atherosclerosis, we plan to investigate a role of apoptosis and glycolysis in macrophage polarization and foam cell formation, the central step in plaque formation. We will employ several pharmacological approaches to alter IEX-1 expression or glycolysis and evaluate its impact on macrophage phenotype and foam cell production. Together, these studies will advance our understanding of how macrophage phenotype regulates atherosclerosis. The results may help develop promising therapeutic or diagnostic approaches for lipid-driven inflammatory conditions such as atherosclerosis, diabetes, and obesity.

巨噬细胞特异性IEX-1 --动脉粥样硬化发病机制的新机制 动脉粥样硬化是一种慢性炎症性疾病，其特征在于脂质在动脉壁中的积聚。 它是美国发病率和死亡率的主要原因。几种免疫细胞参与了 动脉粥样硬化;然而，巨噬细胞在疾病的所有阶段中发挥核心作用。新出现的证据 表明巨噬细胞的数量和表型都影响着 动脉粥样硬化病变已经在动脉粥样硬化斑块中鉴定出几种巨噬细胞亚群， 包括经典激活（CAM），交替激活（AAMs）和Mox基于其不同的基因 表情具有CAM样特征的巨噬细胞在动脉粥样硬化的起始中起着至关重要的作用， 在内皮下空间浸润并促进炎症。它们吞噬脂质，变成泡沫细胞， 形成斑块。相比之下，AAM样巨噬细胞在消退斑块中富集。它们抑制 炎症并表现出减少的泡沫细胞形成。然而，真正的因素，关键的身份 调节巨噬细胞表型的机制仍知之甚少。因此，缺乏有效的 抑制巨噬细胞的促动脉粥样硬化表型以减少动脉粥样硬化的策略。IEX-1是一种压力- 在巨噬细胞中高度表达的诱导基因。我们的初步调查显示，IEX-1 对于动脉粥样硬化的发展至关重要，其缺乏可保护小鼠免受动脉粥样硬化， 影响胆固醇代谢。有趣的是，IEX-1缺陷逆转了巨噬细胞的表型， 在主动脉中从CAM浸润到AAM样状态，对巨噬细胞浸润只有很小的影响。AAM- 偏极化先于动脉粥样硬化斑块的发展。在目前的提案中，我们将 解决了巨噬细胞中IEX-1活性是动脉粥样硬化形成所必需的这一假设。为了解决这个问题，我们 建议使用一种新的小鼠模型，其中IEX-1将选择性地从ApoE上的巨噬细胞中删除， 缺陷背景我们将研究其对动脉粥样硬化斑块形成、主动脉巨噬细胞 表型和炎症状态。此外，为了从机制上了解IEX-1如何有助于 动脉粥样硬化，我们计划研究细胞凋亡和糖酵解在巨噬细胞极化和泡沫中的作用 细胞的形成是斑块形成的中心步骤。我们将采用几种药理学方法， 改变IEX-1表达或糖酵解，并评估其对巨噬细胞表型和泡沫细胞的影响 生产总之，这些研究将促进我们对巨噬细胞表型如何调节 动脉粥样硬化这些结果可能有助于开发有前途的治疗或诊断方法，用于脂质驱动的 炎性病症，如动脉粥样硬化、糖尿病和肥胖症。