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: 10456644
• 负责人: Amir Zarrinpar
• 金额: $ 77.26万
• 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/10456644
• 关键词: ARNTL gene; Address; Affect; Apolipoprotein E; 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; Knock-out; Light; Link; Liver; Maintenance; Metabolic; Metabolic Biotransformation; Metabolic dysfunction; Metabolic syndrome; Microbe; Mus; Myocardial Infarction; Nutrient; Obstructive Sleep Apnea; Pathogenesis; Pathway interactions; Patients; Periodicity; 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; fatty acid oxidation; feeding; gut microbiome; insight; insulin sensitivity; 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.

摘要 据估计，阻塞性睡眠呼吸暂停(OSA)的患病率男性为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。它的 存在显著增加中风和心肌梗死的风险。目前还不清楚OSA或其 特征成分间歇性低氧和高碳酸血症(IHC)可增加心血管疾病，但约 长期以来，人们一直怀疑黛安的节奏。载脂蛋白E基因敲除[ApoE-/-]小鼠模型的建立 现在让我们更好地了解这种疾病如何影响生物钟，以及 昼夜节律不同步，昼夜节律振荡器基因表达的抑制和/或相移(例如 BMAL1，REV-ERBα)和代谢调节剂(如CREB)在IHC诱导的动脉粥样硬化中起作用。昼夜节律 不同步通常发生在摄食模式的改变、生物失调和腔内肌体改变的背景下。 特雷沃斯。因此，这一建议的主要假设是IHC诱导的动脉粥样硬化是由 肠道微生物群动态改变和昼夜节律不同步，可以通过进食进行控制 模式和工程化细菌。 在接下来的五年里，我们将通过追求两个具体目标来解决这一假设。首先，我们将调查- 门摄食模式、肠道微生物群动态和昼夜节律不同步之间的关系-- 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。 提顿。这种摄食方式的变化伴随着肠道微生物群动态的变化，尤其是损失 已知的产生次级胆汁酸(BA)的细菌和夜间BA池的周期性波动。在广告中- 在这种情况下，BAS的排泄增加，激活了法尼类X受体(FXR)，这是一种BA信号转导机制-- NISM对载脂蛋白E-/-小鼠的动脉粥样硬化具有保护作用。我们预料到了这些摄食模式的变化， 肠道微生物组动力学和BA信号会导致昼夜节律不同步。通过使用各种饲喂辅助- 例如限时摄食，我们将确定纠正昼夜节律不同步是否缓解 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 可以影响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。 在基因工程细菌的帮助下。使用可以去结合bas的工程菌，我们将降低流明。 FXR拮抗剂，并确定其是否减轻IHC诱导的动脉粥样硬化。此外，我们还将评估效果。 BA信号和宿主外周昼夜节律的这些变化。最后，我们将执行第一步，以 确定工程菌是否可以成为阻塞性睡眠呼吸暂停综合征患者的潜在治疗剂。总体而言，这 该提案将在IHC诱导的动脉粥样硬化的三个不同组成部分之间架起桥梁：昼夜节律，肠道运动- Crobiome，和BA信号。到最后，这三个组成部分是否相互独立就会变得清晰起来。 IHC诱导的动脉粥样硬化的贡献者，或者如果它们是同一病理生理过程的不同方面。