Enzymatic Control of Trimethylamineoxide (TMAO)Induced Atherosclerosis

描述（由申请人提供）：胆固醇平衡失调显著导致冠心病（CHD），冠心病是美国的主要死因。鉴于哺乳动物不能分解代谢胆固醇，一种称为胆固醇逆向转运（RCT）的多器官过程已经进化到促进胆固醇排泄到粪便中。虽然RCT的过程是很好的赞赏，以防止冠心病的发展，长期以来的理论模型RCT最近受到质疑。最近，我们已经证明，RCT可以通过一种新的途径称为经肠胆固醇排泄（TICE），显着修改RCT的概念框架的领域进行胆汁分泌的情况下。本文提出的研究将全面分析RCT中新参与者（黄素单加氧酶3，FMO3）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，FMO 3驱动的肠道微生物群来源的三甲胺（TMA）酶促转化为氧化三甲基胺（TMAO）已与人类CHD风险显着相关。我们的研究将检查FMO3的底物（TMA）和产物（TMAO）在调节胆汁和非胆汁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是第一个真正的药物靶点，特异性刺激TICE途径，并将提供证据，证明TICE的刺激是否具有动脉粥样硬化保护作用。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RCT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.