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Protective effects of amlexanox against atherosclerosis

氨来呫诺对动脉粥样硬化的保护作用

基本信息

批准号：
10600835
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600835
关键词：
Adhesions Advisory Committees Affect Anabolism Animal Experiments 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 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 Health Hematopoietic stem cells Hyperglycemia Hypertension Hypertriglyceridemia Infiltration Inflammation Inflammatory Insulin Resistance LDL Cholesterol Lipoproteins Lesion Link Liver Macrophage 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 Plasma Positioning Attribute Primary Cell Cultures Proliferating Repression Research Resources Risk Rodent Role Signal Pathway Smooth Muscle Myocytes Societies Stains Stroke TBK1 gene Testing Tissues Up-Regulation absorption amlexanox atherogenesis atheroprotective career cell motility chemokine cholesterol absorption combat cytokine endothelial dysfunction ezetimibe gene synthesis glucose metabolism hepatic gluconeogenesis hepatocyte nuclear factor high risk hypercholesterolemia improved in vivo inhibitor insulin sensitivity kinase inhibitor monocyte non-alcoholic fatty liver disease prevent professor protective effect systemic inflammatory response tenure track transcription factor transcriptome sequencing western diet wound healing

项目摘要

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.

项目概要/摘要代谢综合征，以高胆固醇血症、高甘油三酯血症、高血压为特征，高血糖和胰岛素抵抗已成为现代社会的主要健康风险，并且是死亡原因。目前的抗动脉粥样硬化药物中，他汀类药物和烟酸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人群。依泽麦布和胆汁酸螯合剂的作用不如他汀类药物。因此，需要新的安全有效的药物来对抗这种毁灭性的疾病。我们之前的研究表明氨来呫诺（amlexanox）是 IKK 和 TBK1 的抑制剂，增加胰岛素敏感性并改善葡萄糖代谢。近期初步数据显示 amlexanox 还可减轻 Ldlr-/- 小鼠饮食引起的动脉粥样硬化。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大原因。我们目前的研究有表明 amlexanox 可改善高胆固醇血症、减弱单核细胞增多症并预防主动脉细胞功能障碍。肝脏的 RNA-seq 分析表明氨来呫诺可增加相关基因的表达胆汁酸的合成和分泌，这可以解释氨来呫诺如何降低血液胆固醇。基于根据初步数据，我们假设氨来呫诺可以保护 Ldlr-/- 小鼠免受西方饮食 (WD) 诱导的影响通过增加胆固醇排泄、减少炎症和削弱主动脉细胞来预防动脉粥样硬化功能障碍。该提案的目标是彻底评估 amlexanox 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 amlexanox 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 将识别转录介导氨来呫诺诱导的胆汁酸合成基因表达的因子，并研究如何 amlexanox 调节转录因子的活性。具体 3 将评估 amlexanox 对造血干细胞和祖细胞 (HSPC) 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呫诺如何对单核细胞增多和主动脉细胞功能障碍发挥作用。这申请人的职业目标是成为一名极具竞争力的独立助理候选人通过获得胆固醇代谢和动脉粥样硬化研究方面的额外专业知识，获得教授职位。加州大学圣地亚哥分校出色的研究环境和可用资源，以及在该领域任职的专家候选人的咨询委员会将为申请人实现其职业目标提供模范支持。此外，候选人的主要导师在成功将受训者转变为独立助理教授。在K99/R00奖项的支持下，候选人将处于有利地位竞争终身教授职位。