Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases

深入探讨血管疾病中血管和免疫代谢调节的分子机制

• 批准号: 10543173
• 负责人: Yajaira Suarez
• 金额: $ 94.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543173
• 关键词: Affect; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cells; Cholesterol; Chronic Disease; Disease Progression; Down-Regulation; Endothelial Cells; Exposure to; Foam Cells; Genes; Glycolysis; Goals; Homeostasis; Immune; Immune signaling; Inflammation; Inflammatory; Inflammatory Response; Link; Lipids; Literature; Macrophage; Macrophage Activation; Mesenchymal; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; MicroRNAs; Molecular; Phenotype; Play; Process; Reaction; Regulation; Research; Role; Shapes; Signal Pathway; Smooth Muscle Myocytes; Sterols; Therapeutic; Untranslated RNA; Vascular Diseases; Work; fatty acid oxidation; immune function; inflammatory milieu; innovation; insight; lipid metabolism; programs; response; therapeutic target; vascular inflammation

PROJECT SUMMARY Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic disease characterized by lipid retention and vascular inflammation. Endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages are recognized to have a unique impact on the disease progression. It is recently recognized that specific dysregulation of metabolic signaling pathways contributes to certain aspects of EC, macrophage and SMC homeostasis. For instance, during the process of atherosclerosis, ECs are exposed to a pro-inflammatory milieu that enhances glycolysis and reduces fatty acid oxidation in ECs and predisposes them to undergo mesenchymal transition (EndMT), which may affect plaque stability. The implications of non-coding RNAs, including microRNAs (miRNAs), in cardiovascular disease is well recognized, representing the most rapidly evolving research field. Furthermore, miRNAs have emerged as critical regulators of cellular metabolism (e.g. miR-33) and therefore can directly regulate EC metabolic responses that can determine the progression of atherosclerosis, although this aspect has not been elucidated yet. Moreover, miRNAs can promote the acquisition of mesenchymal markers (e.g. miR-21) that can in turn shape their metabolic response and mesenchymal phenotype, thus affecting EC atherosclerotic phenotype. This has also not been investigated in detail. In this regard, similar mechanisms may be involved in the phenotypic regulation of SMC during atherosclerosis, and need to be explored as well. A vast literature has demonstrated that miRNAs play important roles in macrophage functions by regulating macrophage inflammatory responses and lipid metabolism. Increasing evidence indicates that a substantial crosstalk exists between innate immune signaling and metabolic pathways. Macrophage activation and differentiation prominently feature the modulation of genes involved in general cellular metabolic activities. In this regard, downregulation of cholesterol biosynthetic genes in classically activated macrophages is linked to regulation of inflammatory reactions elicited by macrophages. A critical outstanding question is how the dynamic interplay between cholesterol, cholesterol biosynthetic intermediates and cholesterol derivatives influences macrophage foam cell formation and inflammation, which are key determinants of atherosclerosis progression. On the whole, this research program aims to elucidate different mechanisms that regulate cell-specific metabolic signaling pathways and how they are involved in the progression of atherosclerosis. Targeting cell-specific metabolic processes could become another potential therapeutic targeting strategy for treating metabolic disorders.

项目摘要 动脉粥样硬化是一种以脂质代谢为特征的慢性疾病，是心血管疾病的主要病因 潴留和血管炎症。内皮细胞（EC）、平滑肌细胞（SMC）和巨噬细胞 被认为对疾病进展有独特的影响。最近人们认识到， 代谢信号通路的失调有助于EC、巨噬细胞和SMC的某些方面 体内平衡例如，在动脉粥样硬化的过程中，EC暴露于促炎性因子， 环境，增强糖酵解，减少EC中的脂肪酸氧化，并使其易于发生 间充质转化（EndMT），这可能影响斑块稳定性。非编码RNA的含义， 包括microRNAs（miRNAs），在心血管疾病中是公认的，代表了最迅速的 不断发展的研究领域。此外，miRNA已经成为细胞代谢的关键调节因子（例如， miR-33），因此可以直接调节EC代谢反应，其可以决定 动脉粥样硬化，尽管这方面尚未阐明。此外，miRNAs可以促进 获得间充质标志物（例如miR-21），这反过来可以塑造它们的代谢反应， 间充质表型，从而影响EC动脉粥样硬化表型。这也没有被调查 详细在这方面，类似的机制可能涉及SMC的表型调节过程中， 动脉粥样硬化，也需要探索。大量的文献已经证明， 通过调节巨噬细胞炎症反应在巨噬细胞功能中的重要作用， 脂质代谢越来越多的证据表明，先天性免疫和免疫抑制之间存在着实质性的串扰。 信号和代谢途径。巨噬细胞活化和分化的显著特征是 参与一般细胞代谢活动的基因的调节。在这方面， 经典活化巨噬细胞中的胆固醇生物合成基因与炎症调节有关 由巨噬细胞引起的反应。一个关键的悬而未决的问题是， 胆固醇、胆固醇生物合成中间体和胆固醇衍生物影响巨噬细胞泡沫 细胞形成和炎症，这是动脉粥样硬化进展的关键决定因素。总的来说， 该研究项目旨在阐明调节细胞特异性代谢信号的不同机制 途径以及它们如何参与动脉粥样硬化的进展。靶向细胞特异性代谢 这些过程可能成为治疗代谢紊乱的另一种潜在的治疗靶向策略。