Protective effects of amlexanox against atherosclerosis

氨来呫诺对动脉粥样硬化的保护作用

• 批准号: 10400158
• 负责人: Peng Zhao
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400158
• 关键词: Adhesions; Advisory Committees; Affect; Anabolism; Animals; Aorta; Area; Arterial Fatty Streak; Arteries; Asthma; Atherosclerosis; Attenuated; Award; Bile Acid Biosynthesis Pathway; Bile Acids; Blood; Blood Glucose; CCL2 gene; Cardiovascular Diseases; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cell Proliferation; Cell Wall; Cell physiology; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; Collagen Fibril; Cultured Cells; Data; Development; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Endothelium; Energy Metabolism; Environment; Excretory function; Exhibits; Extracellular Matrix; Faculty; Fasting; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; HNF4A gene; Health; Hematopoietic stem cells; Hyperglycemia; Hypertension; Hypertriglyceridemia; Infiltration; Inflammation; Inflammatory; Insulin Resistance; LDL Cholesterol Lipoproteins; Lesion; Link; Liver; Matrix Metalloproteinases; Mediating; Mentors; Metabolic syndrome; Modernization; Molecular; Monocytosis; Mus; Myocardial Infarction; Necrosis; Nicotinic Acids; Obesity; Organism; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Plant Roots; Plasma; Positioning Attribute; Research; Resources; Risk; Rodent; Role; Signal Pathway; Smooth Muscle Myocytes; Societies; Stains; Stroke; TBK1 gene; Testing; Tissues; Up-Regulation; absorption; amlexanox; atherogenesis; atheroprotective; base; career; cell motility; chemokine; cholesterol absorption; combat; cytokine; endothelial dysfunction; ezetimibe; gene synthesis; glucose metabolism; hepatic gluconeogenesis; high risk; hypercholesterolemia; improved; in vivo; inhibitor; insulin sensitivity; kinase inhibitor; macrophage; monocyte; non-alcoholic fatty liver disease; prevent; professor; protective effect; stem cell function; systemic inflammatory response; tenure track; transcription factor; transcriptome sequencing; western diet; wound healing

PROJECT SUMMARY/ABSTRACT Metabolic syndrome, characterized by hypercholesterolemia, hypertriglyceridemia, hypertension, hyperglycemia and insulin resistance, has become a major health risk in modern society, and are a leading cause of death. Among current anti-atherosclerosis medications, Statins and Niacins increase blood glucose and reduce insulin resistance, making them a high risk for patients with diabetes. Ezetimibe and bile acid sequestrants do not work as well as Statins. Thus, there is a need for new safe and effective drugs to combat this devastating disease. Our previous studies demonstrated that amlexanox, an inhibitor of IKK and TBK1, increases insulin sensitivity and improves glucose metabolism. Recent preliminary data have shown that amlexanox also attenuates diet-induced atherosclerosis in Ldlr-/- mice. Hypercholesterolemia, systemic chronic inflammation and aortic cells dysfunction are three major causes of atherosclerosis. Our current study has indicated that amlexanox improves hypercholesterolemia, attenuates monocytosis and prevents aortic cell dysfunctions. RNA-seq analysis of liver demonstrated that amlexanox increases expression of genes involved in bile acid synthesis and secretion, which may explain how amlexanox reduces blood cholesterol. Based on this preliminary data, we hypothesize that amlexanox protects Ldlr-/- mice from Western diet (WD)-induced atherosclerosis by increasing cholesterol excretion, reducing inflammation and attenuating aortic cell dysfunction. The goals for this proposal are to thoroughly assess the anti-atherosclerosis effects of amlexanox, and uncover the underlying mechanisms. Specific Aim 1 will evaluate the effects of amlexanox on cholesterol metabolism, which include its absorption, excretion and biosynthesis. Specific Aim 2 will identify a transcription factor that mediates amlexanox-induced expression of bile acid synthesis genes, and investigate how amlexanox regulates activity of the transcription factor. Specific 3 will assess effects of amlexanox on proliferation of hematopoietic stem and progenitor cells (HSPCs) and functions of endothelial cells and smooth muscle cells to explain how amlexanox exerts its effects on monocytosis and aortic cell dysfunction. The career goal for the applicant is to become a highly competitive candidate for an independent assistant professor position by gaining additional expertise in the study of cholesterol metabolism and atherosclerosis. The outstanding research environments and available resources at UCSD, along with the experts serving on candidate’s advisory committee will provide exemplary support for the applicant to achieve his career goal. Furthermore, the candidate’s primary mentor has an exceptional record in successful transitioning trainees to independent assistant professors. With the support of the K99/R00 award, the candidate will be well positioned to compete for a tenure track faculty position.

项目总结/摘要 代谢综合征，以高胆固醇血症、高胆固醇血症、高血压为特征， 高血糖症和胰岛素抵抗已成为现代社会的主要健康风险， 死因了在目前的抗动脉粥样硬化药物中，他汀类药物和烟酸类药物会增加血糖 并降低胰岛素抵抗，使他们成为糖尿病患者的高风险。依折麦布和胆汁酸 螯合剂不如他汀类药物有效。因此，需要新的安全有效的药物来对抗 这种毁灭性的疾病。我们先前的研究表明，IKK β和TBK 1的抑制剂氨来萨诺， 增加胰岛素敏感性和改善葡萄糖代谢。最近的初步数据显示， 氨来沙诺还减弱Ldlr-/-小鼠中饮食诱导的动脉粥样硬化。高胆固醇血症，全身性慢性 炎症和主动脉细胞功能障碍是动脉粥样硬化的三个主要原因。我们目前的研究 表明氨来占诺改善高胆固醇血症，减弱单核细胞增多， 功能障碍肝脏的RNA-seq分析表明氨来萨诺增加相关基因的表达 胆汁酸的合成和分泌，这可以解释氨来占诺如何降低血液胆固醇。基于 根据这些初步数据，我们假设氨来萨诺保护Ldlr-/-小鼠免受西方饮食（WD）诱导的 通过增加胆固醇排泄，减少炎症和衰减主动脉细胞 功能障碍该提案的目标是彻底评估氨来诺的抗动脉粥样硬化作用， 并揭示其潜在机制。具体目标1将评估氨来萨诺对胆固醇的影响 代谢包括吸收、排泄和生物合成。具体目标2将确定一个转录 介导氨来沙诺诱导的胆汁酸合成基因表达的因子，并研究如何 氨来诺调节转录因子的活性。特异性3将评估氨来萨诺对 造血干细胞和祖细胞（HSPCs）的增殖以及内皮细胞和平滑肌细胞的功能 肌肉细胞来解释氨来占诺如何发挥其对单核细胞增多症和主动脉细胞功能障碍的影响。的 申请人的职业目标是成为独立助理的高度竞争力的候选人 通过在胆固醇代谢和动脉粥样硬化研究方面获得额外的专业知识，可以获得教授职位。 杰出的研究环境和可用的资源在加州大学圣地亚哥分校，随着专家服务于沿着 候选人的顾问委员会将为申请人提供示范性的支持，以实现其职业目标。 此外，候选人的主要导师在成功地将受训者过渡到 独立助理教授。在K99/R00奖项的支持下，候选人将处于有利地位 竞争终身教职