Enzymatic Control of Trimethylamineoxide (TMAO)Induced Atherosclerosis

描述（由申请人提供）：胆固醇平衡失调对冠心病（CHD）有重要影响，冠心病是美国的主要死亡原因。鉴于哺乳动物不能分解胆固醇，一种被称为逆向胆固醇转运（RCT）的多器官过程已经进化到促进胆固醇排泄到粪便中。尽管随机对照试验在预防冠心病的发展方面得到了很好的认可，但长期存在的随机对照试验理论模型最近受到了质疑。最近，我们已经证明RCT可以通过一种被称为经肠胆固醇排泄（TICE）的新途径在没有胆道分泌的情况下进行，这对该领域显著修改RCT的概念框架提出了挑战。本文提出的研究将全面分析RCT中一个新参与者（Flavin Monooxygenase 3, FMO3）的作用，我们已经在改变TICE的小鼠模型中使用无偏筛选方法确定了该参与者。最近，fmo3驱动的肠道微生物来源的三甲胺（TMA）转化为三甲胺氧化酶（TMAO）与人类冠心病风险显著相关。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，以及这与动脉粥样硬化进展和消退的关系。我们提出的研究有很强的潜力提供临床前证据，证明FMO3是第一个特异性刺激TICE通路的真正药物靶点，并将为刺激TICE是否具有动脉粥样硬化保护作用提供证据。总的来说，这些研究有可能导致预防和/或治疗冠心病的新疗法，并改变我们目前的随机对照试验理论模型。

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.