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.

项目总结 心血管疾病的进展直到最近才被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堆积和炎症的疾病，与 血管内皮细胞的代谢开关。然而，对这一开关的调节还没有完全定义。小非- 编码的microRNAs最近被发现是炎症和新陈代谢的调节因子。例如, MicroRNA-33(miR-33)广泛参与脂类代谢，但其在内皮细胞中的确切作用是 未知。另一种脂代谢的主要调节因子是肝X，其在内皮细胞中的作用尚未确定 受体(LXR)。该提案旨在确定内皮特异性miR-33和LXR如何调节EC 并确定它们的干扰是否会影响动脉粥样硬化的进展。MIR-33可减弱 从细胞中清除胆固醇，另一方面，LXR信号促进这一过程。自.以来 胆固醇滞留与内皮细胞的动脉粥样硬化形成过程有关，这表明 内皮miR-33的致动脉粥样硬化作用和内皮LXR信号的抗动脉粥样硬化作用。另外， 其他miR-33目标包括脂肪酸氧化中的酶(FAO)。因为受到抑制的粮农组织促进了 致动脉粥样硬化的EC过程，如内皮到间质的转变，这强调了另一个促进- MiR-33的致动脉粥样硬化作用。值得注意的是，miR-33和LXR之间有几个可能的串扰点 信号-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 假说是miR-33和LXRs以互补的方式维持胆固醇和血脂 内皮细胞的动态平衡，而它们的任何一个信号的破坏都会使动脉粥样硬化永久存在。这 将通过解决以下具体目标来检验假设：1)研究miR-33在 调节EC脂代谢与动脉粥样硬化；2)阐明LXR信号在EC中的作用 动脉粥样硬化中的代谢和功能障碍。血管内皮细胞特异性的新型小鼠模型的应用 MiR-33或LXRs的缺失将提供对它们在动脉粥样硬化形成中作用的关键洞察。届时，这些目标将是 进一步在体外用最先进的方法组合测试miR-33或LXR的增益或损失 功能，以确定其对EC代谢的调节。这项拟议的研究具有重要意义，因为它 预计将确定内皮新陈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，这个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。