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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.

项目摘要众所周知，肥胖是心血管疾病的驱动因素，但其机制尚不完全清楚了解和干预，打破体重增加和血管疾病之间的联系仍然是一个关键治疗的障碍。NOX 1衍生的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。心血管生理学中的一个基本概念是调节血流以服务于新陈代谢当肥胖症患者的新陈代谢紊乱时，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昼夜节律钟，一种转录调节因子。调节日常代谢节律并编程心血管基因表达以预测这些变化小鼠中生物钟的遗传破坏导致内皮功能障碍和破坏性昼夜节律人类的生活方式导致心血管疾病的发病率较高。血管时钟是如何中断和随后的疾病本体是未知的，并解决这些关键的缺陷，在我们的理解是本申请的重点。来自我们实验室的新数据已经确定了db/db小鼠中广泛的昼夜节律紊乱，表现出严重的肥胖和NOX 1介导的内皮功能障碍。将这些小鼠培育成per luc报告基因一只小鼠显示主动脉中的昼夜节律几乎消失，沿着循环基因减少80 时钟调节基因的表达和减少表达。随后的研究发现，高血糖作为潜在的昼夜节律干扰物，半乳糖凝集素-3和Cezanne作为新的机制，影响NOX 1- eNOS平衡，促进血管功能障碍。基于这些观察，这一提议的核心假设是，肥胖导致血管继发于血管生物钟功能丧失的疾病。我们将在体内测试假设，新的肥胖动物模型与操纵的昼夜节律控制的组成部分，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。