The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis

摘要 据估计，男性阻塞性睡眠呼吸暂停（OSA）的患病率为34%，女性为17% 年龄在30至70岁之间，但在心血管疾病（CVD）患者中更为常见。其 存在显著增加中风和心肌梗塞的风险。目前尚不清楚OSA或其 特征性成分，间歇性缺氧和高碳酸血症（IHC），增加CVD，但中断的大约， 昼夜节律一直被怀疑。OSA小鼠模型（IHC中载脂蛋白E敲除[ApoE-/-]小鼠） 条件）现在使我们能够更好地了解这种疾病如何影响生物钟， 昼夜节律不同步，昼夜节律振荡基因（例如， Bmal 1，Rev-erbα）和代谢调节因子（如CREB）参与了IHC诱导的动脉粥样硬化。昼夜 不同步通常发生在进食模式改变、生态失调和管腔内环境改变的情况下， tabbed。因此，这一建议的主要假设是，IHC诱导的动脉粥样硬化的结果， 改变肠道微生物组动力学和昼夜不同步，这可以通过喂养来控制 模式和工程菌。 在未来五年里，我们将通过追求两个具体目标来解决这一假设。首先，我们将投资- 门进食模式，肠道微生物组动力学和IHC中的昼夜不同步之间的关系- 诱发动脉粥样硬化。我们的初步数据表明，在IHC条件下，ApoE-/-小鼠的摄食模式发生了改变， 是的。这种摄食模式的变化伴随着肠道微生物组动力学的变化，特别是在损失方面。 已知产生次级胆汁酸（BA）和夜间BA池的细菌的周期性波动。在公元- 此外，有增加的BA分泌，激活法尼醇X受体（FXR），BA信号机制， 在ApoE-/-小鼠中对动脉粥样硬化有保护作用的nism。我们预料到了进食模式的变化， 肠道微生物组动力学和BA信号传导将导致昼夜不同步。通过使用各种进料帕拉， digms，如时间限制喂养，我们将确定是否纠正昼夜节律不同步 IHC诱导的动脉粥样硬化。在第二个具体目标中，为了更好地了解肠道微生物组的功能， 可能影响IHC诱导的动脉粥样硬化，我们将通过调节管腔BA池来改变BA信号传导， 工程菌的帮助。使用可以解偶联BA的工程细菌，我们将减少管腔 FXR拮抗剂，并确定它是否能抑制IHC诱导的动脉粥样硬化。此外，我们会评估 这些变化的BA信号和主机周边昼夜节律。最后，我们将执行第一步， 确定工程菌是否可以成为OSA患者的潜在治疗剂。总体而言，这 该提案将桥接IHC诱导的动脉粥样硬化的三个不同组成部分：昼夜节律，肠道微循环， crobiome和BA信号。到最后，这三个组成部分是否是独立的组成部分将是清楚的。 它们是IHC诱导的动脉粥样硬化的贡献者，或者它们是同一病理生理过程的不同方面。

ABSTRACT The prevalence of obstructive sleep apnea (OSA) has been estimated to be 34% for men and 17% for women between 30 and 70 years old, but is far more common among patients with cardiovascular disease (CVD). Its presence significantly increases the risk for stroke and myocardial infarction. It is not clear how OSA, or its characteristic components, intermittent hypoxia and hypercapnia (IHC), increases CVD, but disruption of circa- dian rhythms has long been suspected. Mouse models of OSA (Apoprotein E knockout [ApoE-/-] mice in IHC conditions) now allow us to better understand how this disease could affect the circadian clock and whether circadian dyssynchrony, a dampening and/or phase shift of the expression of circadian oscillator genes (e.g. Bmal1, Rev-erbα) and metabolic regulators (e.g. CREB), contributes to IHC-induced atherosclerosis. Circadian dyssynchrony usually occurs in the setting of alterations in feeding pattern, dysbiosis, and altered luminal me- tabolites. Hence, the main hypothesis of this proposal is that IHC-induced atherosclerosis results from altered gut microbiome dynamics and circadian dyssynchrony, which can be manipulated with feeding pattern and engineered bacteria. Over the next five years, we will address this hypothesis by pursuing two specific aims. First, we will investi- gate the relationship between feeding pattern, gut microbiome dynamics, and circadian dyssynchrony in IHC- induced atherosclerosis. Our preliminary data show that feeding pattern is altered in ApoE-/- mice in IHC condi- tion. This change in feeding pattern is accompanied with changes in gut microbiome dynamics, especially in loss of cyclical fluctuations in bacteria known to produce secondary bile acids (BAs) and nocturnal BA pools. In ad- dition, there is increased excretion of BAs that activate the farnesoid X receptor (FXR), a BA signaling mecha- nism that is protective against atherosclerosis in ApoE-/- mice. We anticipate these changes in feeding pattern, gut microbiome dynamics, and BA signaling will lead to circadian dyssynchrony. By using various feeding para- digms, such as time-restricted feeding, we will determine whether correcting circadian dyssynchrony alleviates IHC-induced atherosclerosis. In the second specific aim, to better understand how gut microbiome functions could affect IHC-induced atherosclerosis, we will change BA signaling by modulating the luminal BA pool using the help of engineered bacteria. Using engineered bacteria that can deconjugate BAs, we will decrease luminal FXR antagonists and determine if it alleviates IHC-induced atherosclerosis. In addition, we will assess the effect of these changes in BA signaling and host peripheral circadian rhythms. Finally, we will perform the first step to determine whether engineered bacteria can be a potential therapeutic agent in patients with OSA. Overall, this proposal will bridge three different components of IHC-induced atherosclerosis: circadian rhythms, the gut mi- crobiome, and BA signaling. By the end, it will be clear whether these three components are independent con- tributors to IHC-induced atherosclerosis, or if they are different facets of the same pathophysiological process.