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：
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
项目类别：
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

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.

项目摘要/摘要代谢综合征，特征是高胆固醇血症，高甘油三酸酯血症，高血压，高血压，高血糖和胰岛素抵抗，已成为现代社会的主要健康风险，是领先的死亡原因。在目前的抗动脉粥样硬化药物中，他汀类药物和烟碱增加了血糖并降低胰岛素抵抗，使其成为糖尿病患者的高风险。 ezetimibe和胆汁酸递延剂不如汀类药物起作用。那是需要新的安全有效的药物来对抗这种毁灭性的疾病。我们以前的研究表明，IKK和TBK1的抑制剂amlexanox，提高胰岛素敏感性并改善葡萄糖代谢。最近的初步数据表明弹药还会减弱饮食诱导的LDLR - / - 小鼠的动脉粥样硬化。高胆固醇血症，全身慢性血症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。我们目前的研究有表明肿瘤毒素可改善高胆固醇血症，减弱单核细胞增多并预防主动脉细胞功能障碍。肝脏的RNA-seq分析表明，肿瘤毒素会增加所涉及的基因的表达在胆汁酸的合成和分泌中，这可以解释氨氨基毒素如何降低血液胆固醇。基于该初步数据，我们假设amlexanox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来增加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，并发现基本机制。具体目标1将评估氨氨基毒素对胆固醇的影响代谢，包括其抽象，排泄和生物合成。特定目标2将确定转录介导氨基烷氧诱导的胆汁酸合成基因表达的因素，并研究如何弹药调节转录因子的活性。特定3将评估amlexanox对造血茎和祖细胞（HSPC）的增殖以及内皮细胞的功能和光滑肌肉细胞解释了氨氨基毒素如何对单核细胞增多症和主动脉细胞功能障碍作用。这申请人的职业目标是成为独立助理的竞争激烈的候选人通过在胆固醇代谢和动脉粥样硬化的研究中获得更多专业知识，教授职位。 UCSD的杰出研究环境和可用资源以及服务的专家候选人的咨询委员会将为申请人提供典范的支持，以实现其职业目标。此外，候选人的主要导师在成功过渡到学员到独立助理教授。在K99/R00奖的支持下，候选人将得到很好的位置争夺任期教师职位。