Enzymatic Control of Trimethylamineoxide (TMAO)Induced Atherosclerosis

三甲胺氧化物 (TMAO) 诱导的动脉粥样硬化的酶控制

• 批准号: 9054913
• 负责人: Jonathan Mark Brown
• 金额: $ 39.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054913
• 关键词: Acute; Amines; Animal Model; Antisense Oligonucleotides; Apolipoprotein E; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Belief; Bile fluid; Biliary; Cause of Death; Cell surface; Cholesterol; Choline; Clinical; Coronary heart disease; Data; Development; Diet; Dietary Supplementation; Drug Targeting; Equilibrium; Event; Excretory function; FMO3; Family member; Feces; Flavins; Future; Gene Expression; Genetic; Goals; Grant; Health; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Ingestion; Knockout Mice; Lead; Left; Levocarnitine; Link; Liver; Mammals; Mediating; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasma; Prevention; Process; Randomized; Role; Signal Transduction; Surrogate Markers; Testing; Theoretical model; Therapeutic; United States; United States National Institutes of Health; atheroprotective; base; drug discovery; feeding; gut microbiota; heart disease prevention; heart disease risk; improved; knock-down; macrophage; mortality; mouse model; novel; novel therapeutics; pre-clinical; prevent; programs; receptor; reverse cholesterol transport; screening; tool; trimethylamine

DESCRIPTION (provided by applicant): Dysregulation of cholesterol balance contributes significantly to coronary heart disease (CHD), the leading cause of death in the United States. Given that mammals cannot catabolize cholesterol, a multi-organ process known as reverse cholesterol transport (RCT) has evolved to facilitate cholesterol excretion into the feces. Although the process of RCT is well appreciated to protect against the development of CHD, the long-standing theoretical model for RCT has recently been called into question. Recently, we have demonstrated that RCT can proceed in the absence of biliary secretion through a novel pathway known as transintestinal cholesterol excretion (TICE), which has challenged the field to significantly modify the conceptual framework of RCT. Studies proposed here will comprehensively analyze the role of a new player in RCT (Flavin Monooxygenase 3, FMO3), that we have identified using unbiased screening approaches in mouse models of altered TICE. Recently, FMO3-driven enzymatic conversion of gut microbiota-derived trimethylamine (TMA) to trimethylamineoxide (TMAO) has been strikingly associated with CHD risk in humans. Our studies will examine the signaling role for FMO3's substrate (TMA) and product (TMAO) in regulating biliary and non-biliary RCT, and how this relates to atherosclerosis progression and regression. Our proposed studies have strong potential to provide preclinical evidence that FMO3 is the first bona fide drug target for specifically stimulating the TICE pathway, and will provide evidence whether stimulation of TICE is atheroprotective. Collectively, these studies have potential to lead to novel therapies for the prevention and/or treatment of CHD, and to transform our current theoretical model of RCT.

描述（由申请人提供）：胆固醇平衡失调会导致冠心病 (CHD)，而冠心病是美国的首要死因。鉴于哺乳动物无法分解代谢胆固醇，一种被称为反向胆固醇转运 (RCT) 的多器官过程已经进化，以促进胆固醇排泄到粪便中。尽管人们普遍认为 RCT 过程可以预防 CHD 的发展，但长期存在的 RCT 理论模型最近受到了质疑。最近，我们证明 RCT 可以在没有胆汁分泌的情况下通过一种称为经肠胆固醇排泄（TICE）的新途径进行，这对该领域提出了显着修改 RCT 概念框架的挑战。这里提出的研究将全面分析随机对照试验（黄素单加氧酶 3，FMO3）中新参与者的作用，我们已经在 TICE 改变的小鼠模型中使用无偏筛选方法确定了该新参与者。最近，FMO3 驱动的肠道微生物衍生的三甲胺 (TMA) 酶促转化为三甲胺氧化物 (TMAO) 与人类冠心病风险显着相关。我们的研究将探讨 FMO3 的底物 (TMA) 和产物 (TMAO) 在调节胆道和非胆道 RCT 中的信号作用，以及其与动脉粥样硬化进展和消退的关系。我们提出的研究很有可能提供临床前证据，证明 FMO3 是第一个专门刺激 TICE 通路的真正药物靶点，并将提供刺激 TICE 是否具有动脉粥样硬化保护作用的证据。总的来说，这些研究有可能带来预防和/或治疗先心病的新疗法，并改变我们当前的随机对照试验理论模型。