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

基本信息

批准号：
10884617
负责人：
Amir Zarrinpar
金额：
$ 6.28万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10884617
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

项目摘要

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% 30 岁至 70 岁之间，但在心血管疾病 (CVD) 患者中更为常见。 OSA 的存在会增加中风和心肌梗塞的风险，目前尚不清楚。间歇性缺氧和高碳酸血症 (IHC) 的特征成分会增加 CVD，但会破坏循环系统。长期以来，人们一直怀疑 IHC 中的 dian 节律小鼠模型（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以及是否昼夜节律不同步，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（例如 CREB）会导致 IHC 诱导的昼夜节律动脉粥样硬化。不同步通常发生在进食模式、生态失调和管腔代谢改变的情况下。因此，该提议的主要假设是 IHC 诱导的动脉粥样硬化是由代谢物引起的。改变肠道微生物群动态和昼夜节律不同步，可以通过喂养来控制模式和工程细菌。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。在 IHC 中确定喂养模式、肠道微生物组动态和昼夜节律不同步之间的关系我们的初步数据表明，在 IHC 条件下，ApoE-/- 小鼠的进食模式发生了改变。喂养模式的这种变化伴随着肠道微生物群动态的变化，尤其是损失。已知产生次级胆汁酸（BA）和夜间胆汁酸池的细菌的周期性波动。此外，BA 的排泄增加，可激活法尼醇 X 受体 (FXR)，这是一种 BA 信号传导机制。我们预计喂养模式会发生这些变化，通过使用不同的喂养方式，肠道微生物群动态和 BA 信号传导将导致昼夜节律不同步。 digms，例如限时喂养，我们将确定纠正昼夜节律失调是否可以缓解 IHC 诱导的动脉粥样硬化的第二个具体目标是更好地了解肠道微生物组的功能。可能会影响 IHC 诱导的动脉粥样硬化，我们将通过使用调节管腔 BA 池来改变 BA 信号传导在工程细菌的帮助下，使用可以解离 BA 的工程细菌，我们将减少管腔。 FXR 拮抗剂并确定它是否可以减轻 IHC 诱导的动脉粥样硬化。此外，我们将评估其效果。 BA 信号传导和宿主外周昼夜节律的这些变化最后，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。该提案将弥合 IHC 诱导的动脉粥样硬化的三个不同组成部分：昼夜节律、肠道菌群到最后，我们就会清楚这三个组成部分是否是独立的。 IHC 诱导的动脉粥样硬化的促成因素，或者它们是同一病理生理过程的不同方面。