IDOL and dyslipidemia in cardiovascular diseases

IDOL 与心血管疾病中的血脂异常

基本信息

批准号：
10451711
负责人：
YUQING Eugene CHEN
金额：
$ 77.39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451711
关键词：
Ablation Address Adverse effects Agonist Alleles Animal Model Antiatherogenic Anticholesteremic Agents Aorta Atherosclerosis Automobile Driving Basic Science Biology Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Combined Modality Therapy Coronary Arteriosclerosis Coronary artery Data Development Diet Disease Management Disease Outcome Down-Regulation Drug Targeting Dyslipidemias Enteral Event Fatty Liver Fatty acid glycerol esters Genes Genetic Transcription Hepatocyte Homeostasis Human Human Genetics Hyperlipidemia Hypertriglyceridemia In Vitro Incidence Inflammation Intervention Knock-out Knowledge Lipids Lipoproteins Liver Low-Density Lipoproteins Mediating Medical Genetics Meta-Analysis Metabolic Pathway Modeling Monkeys Mus Oryctolagus cuniculus Pathway interactions Patients Pharmacology Physiology Plasma Positioning Attribute Primates Process Proteins Proteomics RXR Regulation Research Residual state Risk Role Signal Transduction Sterols Testing Therapeutic Translating Translational Research Triglycerides Ubiquitination Very low density lipoprotein Work apolipoprotein E receptor 2 atherogenesis atherosclerosis risk base cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor cholesterol absorption clinical translation clinically relevant coronary event density drug intolerance epidemiology study ezetimibe feasibility testing genetic epidemiology genetic manipulation genetic variant hypercholesterolemia in vivo induced pluripotent stem cell inhibitor insight lipid metabolism lipidomics loss of function macrophage mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics particle pre-clinical protein expression response small molecule small molecule inhibitor targeted treatment therapeutic target ubiquitin-protein ligase uptake

Ablation Address Adverse effects Agonist Alleles Animal Model Antiatherogenic Anticholesteremic Agents Aorta Atherosclerosis Automobile Driving Basic Science Biology Blood Vessels Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Combined Modality Therapy Coronary Arteriosclerosis Coronary artery Data Development Diet Disease Management Disease Outcome Down-Regulation Drug Targeting Dyslipidemias Enteral Event Fatty Liver Fatty acid glycerol esters Genes Genetic Transcription Hepatocyte Homeostasis Human Human Genetics Hyperlipidemia Hypertriglyceridemia In Vitro Incidence Inflammation Intervention Knock-out Knowledge Lipids Lipoproteins Liver Low-Density Lipoproteins Mediating Medical Genetics Meta-Analysis Metabolic Pathway Modeling Monkeys Mus Oryctolagus cuniculus Pathway interactions Patients Pharmacology Physiology Plasma Positioning Attribute Primates Process Proteins Proteomics RXR Regulation Research Residual state Risk Role Signal Transduction Sterols Testing Therapeutic Translating Translational Research Triglycerides Ubiquitination Very low density lipoprotein Work apolipoprotein E receptor 2 atherogenesis atherosclerosis risk base cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor cholesterol absorption clinical translation clinically relevant coronary event density drug intolerance epidemiology study ezetimibe feasibility testing genetic epidemiology genetic manipulation genetic variant hypercholesterolemia in vivo induced pluripotent stem cell inhibitor insight lipid metabolism lipidomics loss of function macrophage mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics particle pre-clinical protein expression response small molecule small molecule inhibitor targeted treatment therapeutic target ubiquitin-protein ligase uptake

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项目摘要

ABSTRACT Despite a significant reduction of major vascular events through the use of statins, cardiovascular disease (CVD) continues to be the leading cause of death. New strategies to address the residual risks include combination therapy of statins with ezetimibe or PCSK9 inhibition. Recent clinical findings indicate that, although effective in further reducing LDL-C, combination therapies do not proportionally translate in reduction of CV events, likely from the relatively high plasma triglycerides still present. Furthermore, some patients cannot reach the low LDL-C target levels or are drug intolerant and TG treatment is difficult. These challenges highlight the need for new targets for intervention and novel therapeutic approaches for dyslipidemia. In vitro and in mice models, IDOL was identified as an E3 ubiquitin ligase targeting LDLR, VLDLR and ApoER2 for degradation and regulating plasma lipid homeostasis independently of PCSK9. Furthermore, in genetic epidemiology studies IDOL was highly associated with LDL-C and CVD outcomes and loss-of-function alleles result in extremely low LDL-C and reduced CVD risk. Unfortunately, intrinsic differences in IDOL biology between mice and primates, create the need to develop an animal model that better approximates human IDOL biology in order to advance IDOL research into the translational arena. Our preliminary studies indicate that rabbits constitute a better model to test the feasibility of IDOL as a clinically relevant target for hyperlipidemia and CVD. Indeed, unlike in mice, rabbit IDOL is induced in the liver in response to LXR agonists, same as in monkeys and humans. IDOL knock-out rabbits have decreased LDL-C and upon high fat high cholesterol diet, maintain low total cholesterol and low triglycerides. We will test the hypothesis that reduced IDOL protein expression levels or activity -through gene deficiency or small molecule inhibitors- will increase plasma lipid clearance, reduce hypercholesterolemia, hypertriglyceridemia and inflammation, resulting in reduced atherosclerosis. Using IDOL knock-out, heterozygous and wild type rabbits, we will establish IDOL as a therapeutic target for reducing atherosclerosis in Aim 1, to study IDOL contribution to liver-mediated plasma lipid clearance, diet-induced atherosclerosis in aorta and coronary artery and the effects of newly developed small molecule IDOL inhibitors. In Aim 2, we will deepen the characterization of IDOL KO effects of the physiology of lipid handling and using primary rabbit cells we will define IDOL-dependent mechanisms in hepatocytes underlying lipid clearance and the response in vitro to novel IDOL inhibitors. Human iPSC-derived hepatocytes and macrophages combined with gain- and loss-of-function will address conservation of the mechanisms across species. Completion of these aims by leveraging new IDOL rabbit models to overcome the current barriers to advance IDOL translational research will provide compelling evidences and new findings to enable IDOL translational research as a novel feasible target for development of focused interventions for hyperlipidemia and CVD management in order to further reduce the overall global impact of CVD.

抽象的尽管通过他汀类药物大大减少了重大血管事件，但心血管疾病（CVD）仍然是死亡的主要原因。解决剩余风险的新策略包括他汀类药物与Ezetimibe或PCSK9抑制作用的联合疗法。最近的临床发现表明，尽管有效进一步降低LDL-C，但联合疗法并未按比例翻译为还原 CV事件，可能来自相对较高的血浆甘油三酸酯仍然存在。此外，有些患者无法达到低LDL-C目标水平或药物不耐受，TG治疗很困难。这些挑战强调了对血脂异常的新目标和新型治疗方法的需求。体外在小鼠模型中，偶像被确定为靶向LDLR，VLDLR和APOER2的E3泛素连接酶降解和调节血浆脂质稳态独立于PCSK9。此外，在遗传中流行病学研究偶像与LDL-C和CVD结果高度相关以及功能丧失等位基因导致LDL-C极低，CVD风险降低。不幸的是，偶像生物学的内在差异在小鼠和灵长类动物之间，需要开发一种更好地近似人类的动物模型偶像生物学是为了将偶像研究推向转化领域。我们的初步研究表明兔子构成了一个更好的模型，用于测试偶像作为临床相关目标的可行性高脂血症和CVD。实际上，与小鼠不同，在肝脏中诱导兔子偶像，以响应LXR 激动剂，与猴子和人类相同。偶像敲除兔子降低了LDL-C，在高脂上高胆固醇饮食，保持低胆固醇和低甘油三酸酯。我们将检验以下假设偶像蛋白表达水平降低或通过基因缺乏或小分子抑制剂的活性将增加血浆脂质清除率，降低高胆固醇血症，高甘油三酸酯血症和炎症，导致在减少动脉粥样硬化中。使用偶像淘汰，杂合和野生型兔子，我们将建立偶像作为减少AIM 1中动脉粥样硬化的治疗靶点，研究偶像对肝脏介导的贡献血浆脂质清除率，饮食诱导的主动脉和冠状动脉的动脉粥样硬化以及新的作用开发了小分子偶像抑制剂。在AIM 2中，我们将加深偶像KO效应的特征脂质处理和使用原代兔细胞的生理学，我们将定义偶像依赖的机制肝细胞脂质清除率和对新型偶像抑制剂的反应。人IPSC衍生肝细胞和巨噬细胞与功能障碍和功能丧失相结合将解决跨物种的机制。通过利用新的偶像兔模型来完成这些目标当前促进偶像转化研究的障碍将提供令人信服的证据和新发现使偶像转化研究成为开发重点干预措施的新型可行目标高脂血症和CVD管理，以进一步减少CVD的整体全球影响。