Circadian origins of vascular disease in obesity

肥胖症血管疾病的昼夜起源

基本信息

批准号：
10376205
负责人：
David J Fulton
金额：
$ 68.53万
依托单位：
AUGUSTA UNIVERSITY
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：
2019-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376205
关键词：
Amplifiers Animal Model Aorta Blood Glucose Blood Pressure Blood Vessels Blood flow Breeding Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Circadian Dysregulation Circadian Rhythms Circadian gene expression Data Disease Endothelium Equilibrium Event Exhibits Exposure to Functional disorder Galectin 3 Gene Expression Genes Genetic Genetic Models Genetic Transcription Glucose Glucose Intolerance Hindlimb Human Hyperglycemia Hyperphagia Hypertension Impairment In Vitro Incidence Inflammation Inflammatory Injury Intervention Laboratories Life Style Ligation Link Measurement Mediating Metabolic Metabolism Mus Nutrient Obese Mice Obesity Ontology Outcome Oxidants Perfusion Periodicity Pharmacology Precipitating Factors Prevention Recovery Reporter Secondary to Services Signal Transduction Stress Superoxides Testing Therapeutic Thinness Transgenes Transgenic Mice Up-Regulation Variant Vascular Diseases Vascular Endothelium Weight Gain angiogenesis barrier to care base cardiovascular disorder risk circadian circadian pacemaker db/db mouse endothelial dysfunction improved in vivo loss of function mouse model nobiletin novel oxidant stress preservation programs receptor for advanced glycation endproducts response

项目摘要

PROJECT SUMMARY It is well known that obesity drives cardiovascular disease, but the mechanisms involved are incompletely understood and interventions that break the links between weight gain and vascular disease remain a critical barrier to treatment. Upregulation of NOX1-derived oxidants is a key mechanism of endothelial dysfunction in obesity but the factors precipitating this impairment are unknown. A fundamental concept in cardiovascular physiology is that blood flow is regulated to service metabolism and when metabolism is deranged in obesity, this relationship breaks down and cardiovascular function falters. A major link between cardiovascular function and metabolic demand is the circadian clock, a transcriptional network that regulates daily metabolic rhythms and programs cardiovascular gene expression to anticipate these changes. Genetic disruption of the clock in mice results in endothelial dysfunction and disruptive circadian lifestyles in humans leads to a higher incidence of cardiovascular disease. How the vascular clock becomes disrupted and the subsequent ontology of disease are unknown and resolving these critical deficits in our understanding is the focus of this application. New data from our laboratories have identified extensive circadian disruption in the db/db mouse, which exhibits profound obesity and NOX1-mediated endothelial dysfunction. Breeding these mice to a per luc reporter mouse revealed near abrogation of circadian rhythms in the aorta along with an 80% reduction in cyclic gene expression and diminished expression of clock regulated genes. Subsequent studies identified exaggerated hyperglycemia as a potential circadian disruptor and Galectin-3 and Cezanne as novel mechanisms that may influence NOX1 – eNOS balance to promote vascular dysfunction. Based on these observations, the core hypothesis of this proposal is that obesity causes vascular disease secondary to loss of function of the vascular circadian clock. We will test hypothesis in vivo in novel animal models of obesity with manipulated components of circadian control and in vitro to identify new cellular mechanisms that may be targets for the treatment of vascular disease in obesity.

项目概要众所周知，肥胖会导致心血管疾病，但其具体机制尚不完全清楚。打破体重增加与血管疾病之间联系的干预措施仍然至关重要 NOX1 衍生氧化剂的上调是内皮功能障碍的关键机制。肥胖，但导致这种损害的因素尚不清楚。心血管生理学的一个基本概念是调节血流以服务新陈代谢当肥胖导致新陈代谢紊乱时，这种关系就会破裂，心血管功能就会减弱。心血管功能和代谢需求之间的主要联系是生物钟，它是一种转录机制调节日常代谢节律并编程心血管基因表达以预测这些的网络小鼠生物钟的基因破坏导致内皮功能障碍和昼夜节律紊乱。人类的生活方式导致心血管疾病的发病率更高。被破坏和随后的疾病本体论是未知的，并解决我们的这些关键缺陷理解是这个应用程序的重点。我们实验室的新数据发现 db/db 小鼠的昼夜节律受到广泛破坏，这表现出严重的肥胖和 NOX1 介导的内皮功能障碍将这些小鼠与 per luc 报告者进行繁殖。小鼠的主动脉昼夜节律几乎消失，并且循环基因减少了 80% 随后的研究发现时钟调节基因的表达和表达减少。高血糖是一种潜在的昼夜节律干扰物，Galectin-3 和 Cezanne 是可能的新机制影响NOX1-eNOS平衡促进血管功能障碍。基于这些观察，该提案的核心假设是肥胖导致血管疾病继发于血管生物钟功能丧失的疾病我们将在体内检验假设。新颖的肥胖动物模型，具有昼夜节律控制的操纵成分，并在体外鉴定新的细胞机制可能是治疗肥胖症血管疾病的目标。