Novel Transcriptional & Post-Transcriptional Regulators of Endothelial Metabolism in Atherosclerosis

小说转录

• 批准号: 10389265
• 负责人: Kathryn Citrin
• 金额: $ 4.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389265
• 关键词: ATP binding cassette transporter 1; Address; Affect; Agonist; Anti-Inflammatory Agents; Antiatherogenic; Atherosclerosis; Attenuated; Behavior; Binding; Biogenesis; Cardiovascular Diseases; Cell physiology; Cells; Cellular Metabolic Process; Cholesterol; Data; Elements; Endothelial Cells; Endothelium; Enzymes; Excision; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Goals; Hepatic; High Density Lipoproteins; Homeostasis; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Label; Ligands; Link; Lipids; Literature; Liver X Receptor; Maintenance; Maps; Mesenchymal; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; MicroRNAs; Mission; Molecular; Mus; Nitric Oxide; Nuclear Receptors; Oxidation-Reduction; Pathway interactions; Permeability; Phenotype; Physiological; Post-Transcriptional Regulation; Process; Proteins; Proteomics; Public Health; Receptor Signaling; Regulation; Research; Role; Scheme; Signal Transduction; Sterols; Stimulus; Testing; Transcriptional Regulation; United States National Institutes of Health; Untranslated RNA; Vascular Diseases; atherogenesis; atheroprotective; base; cell type; cytokine; experimental study; fatty acid oxidation; gene network; genomic data; in vitro testing; insight; lipid metabolism; loss of function; macrophage; metabolic phenotype; metabolomics; mouse model; neglect; novel; oxidation; prevent; response; shear stress; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; vascular inflammation

PROJECT SUMMARY The progression of cardiovascular disease has only recently been noted to involve changes in endothelial (EC) metabolism. Atherosclerosis, a disease of vascular lipid accumulation and inflammation, is linked to a metabolic switch of the endothelium. However, the regulation of this switch is incompletely defined. Small non- coding microRNAs have recently been identified as regulators of inflammation and metabolism. For example, microRNA-33 (miR-33) has been extensively implicated in lipid metabolism, yet its precise role in ECs is unknown. Another master regulator of lipid metabolism, whose role in ECs is yet to be defined, is Liver X Receptor (LXR). This proposal seeks to determine how endothelial-specific miR-33 and LXR regulate EC metabolism and determine if their disruption affects atherosclerotic progression. miR-33 attenuates the removal of cholesterol from cells while on the other hand LXR signaling promotes this process. Since cholesterol retention is implicated in atherogenic processes in the endothelium, this suggests a pro- atherogenic role for endothelial miR-33 and an anti-atherogenic role for endothelial LXR signaling. Additionally, other miR-33 targets include enzymes in fatty acid oxidation (FAO). Since dampened FAO promotes atherogenic EC processes such as the Endothelial to Mesenchymal Transition, this emphasizes another pro- atherogenic role of miR-33. Notably, there are several points of possible crosstalk between miR-33 and LXR signaling – namely that LXR can potentially regulate miR-33 expression and that the miR-33 targets include LXR-induced genes – suggesting an interplay between their effects on metabolism. Therefore, the central hypothesis is that miR-33 and LXRs operate in complementary fashions to maintain cholesterol and lipid homeostasis in ECs, and that disruption of either of their signaling perpetuates atherosclerosis. This hypothesis will be tested by addressing the following specific aims: 1) Investigate the role of miR-33 in modulating EC lipid metabolism and atherosclerosis; 2) Delineate the contribution of LXR signaling to EC metabolism and dysfunction in atherosclerosis. The use of novel mouse models with endothelial-specific deletion of miR-33 or the LXRs will provide key insight into their role in atherogenesis. These aims will then be further tested in vitro with a combination of state-of-the-art approaches upon miR-33 or LXR gain- or loss-of- function to determine their regulation of EC metabolism. The proposed research is significant because it is expected to identify two critical cell-autonomous regulators of endothelial metabolism and atherosclerosis. Long-term, the goal of this project is to deepen our understanding of the regulation of EC metabolism and identify novel regulators that can be therapeutically targeted in cardiovascular disease.

项目摘要 心血管疾病的进展只是最近才注意到涉及内皮细胞（EC）的变化， 新陈代谢.动脉粥样硬化是一种血管脂质积聚和炎症的疾病， 内皮的代谢开关。然而，该开关的调节不完全定义。小非- 编码microRNA最近被鉴定为炎症和代谢的调节剂。比如说， microRNA-33（miR-33）广泛参与脂质代谢，但其在EC中的确切作用尚不清楚。 未知另一个脂质代谢的主要调节剂是肝脏X，其在EC中的作用尚未确定 受体（LXR）。该提案旨在确定内皮特异性miR-33和LXR如何调节EC 代谢，并确定它们的破坏是否影响动脉粥样硬化的进展。miR-33减弱了 从细胞中去除胆固醇，而另一方面LXR信号传导促进这一过程。以来 胆固醇潴留与内皮的致动脉粥样硬化过程有关，这表明 内皮miR-33的致动脉粥样硬化作用和内皮LXR信号传导的抗动脉粥样硬化作用。此外，本发明还 其它miR-33靶包括脂肪酸氧化（FAO）中的酶。由于粮农组织促进 致动脉粥样硬化EC过程，如内皮细胞间质转化，这强调了另一个促 miR-33的致动脉粥样硬化作用。值得注意的是，在miR-33和LXR之间存在几个可能的串扰点。 信号传导-即LXR可以潜在地调节miR-33表达，并且miR-33靶点包括 LXR诱导的基因-表明它们对代谢的影响之间存在相互作用。因此中央 一种假说是miR-33和LXR以互补方式运作，以维持胆固醇和脂质 EC中的稳态以及它们的信号传导的破坏会使动脉粥样硬化持续存在。这 将通过解决以下具体目标来检验假设：1）研究miR-33在以下方面的作用 2）阐明LXR信号通路对EC脂质代谢和动脉粥样硬化的作用 动脉粥样硬化的代谢和功能障碍。使用具有内皮特异性的新型小鼠模型 miR-33或LXR的缺失将提供对它们在动脉粥样硬化形成中的作用的关键了解。这些目标将是 进一步在体外测试了miR-33或LXR获得或丧失的最新方法的组合， 功能，以确定其调节EC代谢。这项研究之所以重要，是因为 有望确定内皮代谢和动脉粥样硬化的两个关键细胞自主调节剂。 从长远来看，本项目的目标是加深我们对EC代谢调节的理解， 鉴定可以在心血管疾病中治疗靶向的新型调节剂。