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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.

项目总结