Mechanisms of Atherosclerosis in Alcohol Intake

饮酒导致动脉粥样硬化的机制

基本信息

批准号：
8773243
负责人：
James Haorah
金额：
$ 18.18万
依托单位：
NEW JERSEY INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773243
关键词：
3-nitrotyrosine Accounting Address Alcohol abuse Alcohol consumption Alcohols Animal Model Antioxidants Arterial Fatty Streak Arteries Atherosclerosis Biochemical Blood Blood - brain barrier anatomy Blood Cells Blood Pressure Blood Vessels Blood capillaries Brain Brain imaging Cardiovascular system Caspase Caspase-1 Cause of Death Cell Adhesion Cell Culture Techniques Cells Cerebral Atheroscleroses Cerebrum Cholesterol Chronic Clinical Complement Crystal Formation Crystallization Cyclodextrins Data Deposition Development Disease Dose Endothelial Cells Ethanol Extravasation Failure Fatty Acids Figs - dietary Filipin Functional Magnetic Resonance Imaging Gene Silencing Goals Health Health Benefit Human Hypertension Immune Immunohistochemistry Incidence Infarction Infiltration Inflammation Injury Interleukin-18 Ischemic Stroke Joints Kinetics Knowledge Levocarnitine Acetyl Magnetic Resonance Imaging Matrix Metalloproteinases Mediating Molecular Nonesterified Fatty Acids Oxidoreductase Plasma Preclinical Testing Prevention Preventive Risk Risk Factors Serum Signal Pathway Site Stroke Techniques Temperature Testing Therapeutic Time Whole Blood alcohol effect atorvastatin brain cell brain tissue capillary cell type chronic alcohol ingestion disability human disease improved in vivo imaging inhibitor/antagonist innovation interleukin-1beta-converting enzyme inhibitor macrophage nanoparticle oxidative damage pressure prevent protective effect research study response

项目摘要

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and the most prevalent cause of permanent disability. This application evolves from the findings that chronic alcohol use is strongly associated with atherosclerosis and stroke with not well define underlying molecular/cellular mechanisms. Here, we propose to examine the hypothesis that immune cell adhesion and cholesterol deposit at the site of oxidative injury in capillary walls causes formation cholesterol crystals (CC) to activate NLRP3 inflammasome for induction of atherosclerosis in heavy chronic alcohol intake. The clinical relevant of this application is that Joint therapy of acetyl-L-carnitine (ALC) and Lipitor can prevent this alcohol-elicited CC formation and atherosclerotic lesions. We will address this innovative idea in our recently developed unique animal model of human disease with two objectives. Our first objective is to examine if immune cell adhesion and cholesterol deposit at the vasculature enhances CC formation, NLRP3 activation and atherosclerotic lesions in response to dose-time-/and temperature-dependent effects of alcohol. After establishing this kinetic profile, we will then address the molecular mechanisms of CC-induced activation of NLRP3 and downstream caspase 1 signaling pathways in primary human brain endothelial cell culture. Our second objective is to evaluate if a joint therapy of ALC/Lipitor can reverse the early development of atherosclerosis in chronic alcohol intake. This will assess the protective effect of ALC/Lipitor from alcohol-induced atherosclerotic bulging, brain infarct volume, intracranial blood pressure and in vivo imaging of CC using cyclodextrin nanoparticles specific to CC by MR brain imaging.

描述（由申请人提供）：中风是第三大死因，也是导致永久性残疾的最普遍原因。该应用源于以下发现：长期饮酒与动脉粥样硬化和中风密切相关，但尚未很好地定义潜在的分子/细胞机制。在此，我们建议检验以下假设：毛细血管壁氧化损伤部位的免疫细胞粘附和胆固醇沉积会导致胆固醇晶体（CC）的形成，从而激活NLRP3炎症小体，从而在长期大量饮酒时诱导动脉粥样硬化。本申请的临床相关性在于，乙酰左旋肉碱(ALC)和立普妥联合治疗可以预防这种酒精引起的CC形成和动脉粥样硬化病变。我们将在最近开发的独特的人类疾病动物模型中解决这一创新想法，有两个目标。我们的第一个目标是检查脉管系统中的免疫细胞粘附和胆固醇沉积是否会增强 CC 形成、NLRP3 激活和动脉粥样硬化病变，以响应酒精的剂量-时间/和温度依赖性作用。建立此动力学曲线后，我们将探讨原代人脑内皮细胞培养物中 CC 诱导的 NLRP3 和下游 caspase 1 信号通路激活的分子机制。我们的第二个目标是评估 ALC/立普妥联合治疗是否可以逆转长期饮酒引起的动脉粥样硬化的早期发展。这将评估 ALC/立普妥对酒精引起的动脉粥样硬化膨出、脑梗死体积、颅内血压的保护作用，以及使用针对 CC 的环糊精纳米颗粒通过 MR 脑成像对 CC 进行体内成像。