The Role of Altered Luminal Dynamics in OSA-Induced Atherosclerosis

管腔动力学改变在 OSA 诱发的动脉粥样硬化中的作用

• 批准号: 10657460
• 负责人: Amir Zarrinpar
• 金额: $ 69.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657460
• 关键词: ARNTL gene; Affect; Apoproteins; Arrhythmia; Atherosclerosis; Bacteria; Bile Acids; CREB1 gene; Cardiovascular Diseases; Cessation of life; Characteristics; Circadian Dysregulation; Circadian Rhythms; Data; Disease; Ecology; Engineering; Environment; Excretory function; FRAP1 gene; Feeding Patterns; Foundations; Functional disorder; Genes; Homeostasis; Hormones; Hypercapnia; Hypoxia; Insulin Resistance; Knock-in; Knockout Mice; Link; Liver; Maintenance; Metabolic; Metabolic Biotransformation; Metabolic dysfunction; Metabolic syndrome; Microbe; Myocardial Infarction; Nutrient; Obstructive Sleep Apnea; Pathogenesis; Pathway interactions; Patients; Peripheral; Phase; Phenotype; Physiology; Play; Prevalence; Process; Research; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Structure; Techniques; Testing; Therapeutic; Therapeutic Agents; Time-restricted feeding; Tissues; United States; Woman; antagonist; cardiometabolism; cardiovascular risk factor; circadian; circadian pacemaker; cytokine; dysbiosis; farnesoid X-activated receptor; fatty acid oxidation; feeding; gut microbiome; insight; insulin sensitivity; light entrainment; men; metabolome; mouse model; receptor; stroke risk; targeted treatment

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.

抽象的 阻塞性睡眠呼吸暂停（OSA）的患病率估计为男性34％，女性为17％ 在30至70岁之间，但在心血管疾病（CVD）患者中更为普遍。 存在显着增加了中风和心肌梗塞的风险。目前尚不清楚OSA或ITS 特征成分，间歇性缺氧和高碳酸血症（IHC）增加了CVD，但大约的破坏 长期以来一直怀疑戴安·节奏。 OSA的鼠标模型（apoprotoin e基因敲除[apoE - / - ] IHC中的小鼠 现在条件）现在让我们更好地了解这种疾病如何影响昼夜节律，以及是否是否 昼夜节律症状，昼夜振荡子基因表达的阻尼和/或相移（例如， BMAL1，REV-ERBα）和代谢调节剂（例如CREB）有助于IHC诱导的动脉粥样硬化。昼夜节律 异位障碍通常发生在喂养模式，营养不良和腔内变化改变的环境中 土豆片。因此，该提议的主要假设是IHC诱导的动脉粥样硬化是由 改变肠道微生物组动力学和昼夜节律障碍，可以用喂养来操纵 模式和工程细菌。 在接下来的五年中，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 闸门在IHC- 诱导动脉粥样硬化。我们的初步数据表明，在IHC Condi的APOE - / - 小鼠中的喂养模式发生了变化 tion。进食模式的这种变化伴随着肠道微生物组动力学的变化，尤其是损失 在已知产生次级胆汁酸（BAS）和夜间BA池的细菌中周期性波动的。在广告中 dition，激活Farnesoid X受体（FXR）的BAS的排泄增加，BA信号机械 - 在APOE - / - 小鼠中受到保护的动脉粥样硬化。我们预计喂养方式上会有这些变化， 肠道微生物组动力学和BA信号传导将导致昼夜节律障碍。通过使用各种喂养para- DIGMS，例如时间限制的喂养，我们将确定是否纠正昼夜节律障碍 IHC引起的动脉粥样硬化。在第二个特定目标中，以更好地了解肠道微生物组的功能 可能影响IHC引起的动脉粥样硬化，我们将使用使用Luminal BA池来更改BA信号传导 使用可以解轭碱的工程细菌，我们将减少管腔 FXR拮抗剂并确定它是否减轻了IHC诱导的动脉粥样硬化。此外，我们将评估效果 在BA信号传导和宿主外围昼夜节律中的这些变化中。最后，我们将执行第一步 确定工程细菌是否可以成为OSA患者的潜在治疗剂。总体而言，这 提案将桥接IHC引起的动脉粥样硬化的三个不同组成部分：昼夜节律，肠道。 怪异和BA信号传导。最后，可以清楚地清楚这三个组成部分是否是独立的 IHC的支流引起的动脉粥样硬化，或者如果它们是相同病理生理过程的不同方面。