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

小说转录

• 批准号: 10683705
• 负责人: Kathryn Citrin
• 金额: $ 4.77万
• 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/10683705
• 关键词: ATP binding cassette transporter 1; Address; Affect; 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; Gene Proteins; Generations; Genes; Genetic; Genetic Transcription; Goals; Hepatic; High Density Lipoproteins; Homeostasis; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Label; Ligands; Link; Lipids; Literature; Liver X Receptor; Macrophage; 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; Proteomics; Public Health; Receptor Signaling; Regulation; Repression; Research; Role; Scheme; Signal Transduction; Sterols; Stimulus; Testing; United States National Institutes of Health; Untranslated RNA; Vascular Diseases; atherogenesis; atheroprotective; cell type; cytokine; experimental study; fatty acid oxidation; gene network; genomic data; in vitro testing; insight; lipid metabolism; loss of function; metabolic phenotype; metabolomics; mouse model; neglect; novel; oxidation; posttranscriptional; prevent; programs; receptor; 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.

项目概要 直到最近才注意到心血管疾病的进展涉及内皮细胞 (EC) 的变化 代谢。动脉粥样硬化是一种血管脂质堆积和炎症的疾病，与 内皮的代谢转换。然而，该开关的调节尚未完全定义。小非 编码 microRNA 最近被确定为炎症和代谢的调节因子。例如， 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。脂质代谢的另一个主要调节因子是肝脏 X，其在 EC 中的作用尚未明确。 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会影响动脉粥样硬化的进展。 miR-33 减弱 从细胞中去除胆固醇，而另一方面 LXR 信号传导则促进这一过程。自从 胆固醇滞留与内皮细胞的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， 其他 miR-33 靶标包括脂肪酸氧化酶 (FAO)。由于粮农组织推动的 致动脉粥样硬化的 EC 过程，例如内皮细胞到间质细胞的转变，这强调了另一个亲 miR-33 的致动脉粥样硬化作用。值得注意的是，miR-33 和 LXR 之间有几个可能存在串扰的点 信号传导——即 LXR 可以潜在地调节 miR-33 的表达，并且 miR-33 的靶标包括 LXR 诱导的基因——表明它们对新陈代谢的影响之间存在相互作用。因此，中央 假设 miR-33 和 LXR 以互补的方式运作以维持胆固醇和脂质 EC 中的稳态，并且其任何一个信号传导的破坏都会使动脉粥样硬化永久化。这 将通过解决以下具体目标来检验假设：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 的缺失将为了解它们在动脉粥样硬化形成中的作用提供关键见解。这些目标随后将是 结合最先进的方法在体外进一步测试 miR-33 或 LXR 的增益或缺失 功能来确定它们对 EC 代谢的调节。拟议的研究意义重大，因为它 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因子。 从长远来看，该项目的目标是加深我们对 EC 代谢调节和 确定可作为心血管疾病治疗靶点的新型调节剂。