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

小说转录

基本信息

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
项目类别：
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

项目摘要

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) 的变化动脉粥样硬化是一种血管脂质堆积和炎症的疾病，与代谢有关。然而，这种开关的调节尚不完全确定。例如，编码 microRNA 最近被确定为炎症和代谢的调节因子。 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另一个未知的脂质代谢主要调节因子是肝脏 X，其在 EC 中的作用尚未确定。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 miR-33 减弱动脉粥样硬化的进展。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。胆固醇滞留与内皮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。其他 miR-33 靶标包括脂肪酸氧化酶 (FAO)，因为FAO 的促进作用受到抑制。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 的动脉粥样硬化作用值得注意的是，miR-33 和 LXR 之间可能存在多个交叉点。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。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。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中的代谢和功能障碍的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。进一步结合最先进的方法在体外测试 miR-33 或 LXR 的增益或缺失确定它们对 EC 代谢的调节作用。这项研究意义重大，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。