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 直到最近才发现心血管疾病的进展涉及内皮变化（EC） 代谢。动脉粥样硬化是一种血管脂质积累和炎症疾病，与A有关 内皮的代谢开关。但是，该开关的调节未完全定义。小非 - 编码microRNA最近被确定为注射和代谢的调节剂。例如， microRNA-33（miR-33）已广泛与脂质代谢有关，但其在EC中的精确作用是 未知。肝脏代谢的另一个主要调节剂，其在EC中的作用尚未定义，是肝脏X 受体（LXR）。该建议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削弱了 另一方面，从细胞中去除胆固醇，而LXR信号传导促进了这一过程。自从 胆固醇的保留率在佛教中的动脉粥样硬化过程中暗示，这表明 内皮miR-33的动脉粥样硬化作用，以及内皮LXR信号传导的抗动脉粥样硬化作用。此外， 其他miR-33靶标包括脂肪酸氧化（FAO）中的酶。自该死的粮农组织促销 动脉粥样硬化过程，例如内皮到间充质转变的过程，这强调了另一种促进 miR-33的动脉粥样硬化作用。值得注意的是，miR-33和LXR之间有几个可能的串扰点 信号传导 - 即LXR可以潜在地调节miR-33表达，而miR-33靶标包括 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 假设是miR-33和LXR在完整时尚中运行以维持胆固醇和脂质 EC中的稳态以及它们的任何一个信号传导的破坏都使动脉粥样硬化延续。这 假设将通过解决以下特定目的来检验：1）研究miR-33在 调节EC脂质代谢和动脉粥样硬化； 2）描述LXR信号对EC的贡献 动脉粥样硬化中的代谢和功能障碍。使用新颖的鼠标模型与内皮特异性 miR-33或LXR的缺失将为它们在动脉粥样硬化中的作用提供关键的见解。这些目标将是 在miR-33或LXR增益或丧失时，通过最先进的方法结合了进一步的体外测试。 确定其调节EC代谢的功能。拟议的研究很重要，因为它是 预计将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。 长期，该项目的目标是加深我们对EC代谢的调节的理解 确定可以在心血管疾病中热针对的新型调节剂。