Multiscale Analysis of Inter-Clock Communication

时钟间通信的多尺度分析

基本信息

批准号：
8301637
负责人：
GARRET A FITZGERALD
金额：
$ 49.04万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301637
关键词：
Ablation Address Adipocytes Adrenal Glands Animal Model Behavior Behavioral Biology Blood Pressure Blood Vessels Brain Bypass Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell physiology Cells Circadian Rhythms Communication Data Defect Dependence Development Diabetes Mellitus Disease Distal Endothelial Cells Energy Metabolism Enzymes Exons Fatty acid glycerol esters Feeding behaviors Gene Deletion Gene Mutation Genetic Genetic Transcription Genome Glucose Glucose Intolerance Grant Health Heart Diseases Homeostasis Hour Hydroxymethylglutaryl-CoA reductase Hypothalamic structure Inflammation Inflammatory Insulin Resistance Internet Kidney Knockout Mice Lead Lipids Liver Luciferases Maps Mediating Messenger RNA Metabolic Metabolic syndrome Metabolism Modeling Molecular Motor Activity Mus Muscle function Neuraxis Neurons Organ Pathway interactions Peripheral Phase Phenotype Physiological Physiology Play Process Proteins Regulation Research Role Signaling Molecule Smooth Muscle Myocytes Stimulus System Testing Therapeutic Time Tissue Harvesting Tissues Vascular Endothelial Cell abstracting atherogenesis behavior influence blood glucose regulation body system cell type cholesterol biosynthesis circadian pacemaker feeding high risk information processing insulin sensitivity knockout gene macrophage mouse model response scaffold shift work suprachiasmatic nucleus

项目摘要

Abstract The circadian clock regulates many aspects of physiology including metabolism and cardiovascular function. The past decade of research has seen the development of a scaffold model of oscillator function in which the suprachiasmatic nucleus of the hypothalamus harbors a "master clock" and orchestrates peripheral oscillators present in most major organ systems. These central and peripheral oscillator systems generate a cascade of circadian transcriptional rhythms that ultimately culminate in observed physiological and behavioral oscillations. Genetic disruption of this organization in animal models results in pathophysiological consequences such as glucose intolerance and insulin resistance, components of the metabolic syndrome seen in people at high risk for cardiovascular disease. We present compelling evidence that communication between clocks is more sophisticated and can involve peripheral-to-peripheral and peripheral-to-central clock communication. Here we test the central hypothesis that communication between peripheral and central oscillators is bidirectional and that peripheral oscillators may directly influence each others' function. Using cell type specific conditional mouse models in which Bmal1, a required component of the oscillator, is deleted, we will use physiological and systems approaches to test the hypothesis that oscillator function in endothelial cells regulates vascular smooth muscle function (and vice versa) and influences diurnal variation in blood pressure, thrombogenesis, and locomotor activity (Specific Aim 1). We will also test the hypothesis that oscillator function in adipocytes regulates macrophage function (and vice versa) and influences glucose homeostasis, response to inflammatory stimuli, and feeding rhythms (Specific Aim 2). Furthermore, we propose testing a mechanistic hypothesis that cell type specific disruption of oscillator function results in oscillator abnormalities in nearby cells, and that this disruption propagates to the liver, adrenal, kidneys, and the brain (Specific Aim 3). Finally, using systems approaches we will examine network level changes provoked by genetic disruption of oscillator function in specific cell types and begin to probe network to network conveyance of circadian information as well as identify candidate signaling molecules (Specific Aim 4).

抽象的生物钟调节生理学的许多方面，包括新陈代谢和心血管功能。过去十年的研究见证了支架的发展振荡功能模型，其中下丘脑的视交叉上核具有 “主时钟”并协调大多数主要器官系统中存在的外围振荡器。这些中枢和外周振荡器系统产生一系列昼夜节律转录最终导致观察到的生理和行为波动的节律。遗传动物模型中该组织的破坏会导致病理生理学后果例如葡萄糖不耐受和胰岛素抵抗，代谢综合征的组成部分见于心血管疾病高危人群。我们提供令人信服的证据表明时钟之间的通信更加复杂，可能涉及外设到外设以及外设到中央时钟通信。在这里我们检验中心假设外围振荡器和中央振荡器之间的通信是双向的，并且外围振荡器可能直接影响彼此的功能。使用特定的细胞类型在条件小鼠模型中，删除了振荡器所需的 Bmal1 组件，我们将使用生理学和系统方法来检验振荡器功能的假设内皮细胞调节血管平滑肌功能（反之亦然）并影响血压、血栓形成和运动活动的昼夜变化（具体目标 1）。我们还将检验脂肪细胞中的振荡功能调节巨噬细胞功能的假设（反之亦然）并影响葡萄糖稳态、对炎症刺激的反应，以及喂养节奏（具体目标 2）。此外，我们建议检验机械假设细胞类型特异性的振荡器功能破坏会导致附近的振荡器异常细胞，并且这种破坏会传播到肝脏、肾上腺、肾脏和大脑（具体目标3）。最后，使用系统方法，我们将检查由以下因素引起的网络级别变化：特定细胞类型中振荡器功能的遗传破坏并开始探测网络昼夜节律信息的网络传递以及识别候选信号分子（具体目标 4）。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bmal1 Deletion in Myeloid Cells Attenuates Atherosclerotic Lesion Development and Restrains Abdominal Aortic Aneurysm Formation in Hyperlipidemic Mice.

骨髓细胞中的 Bmal1 缺失可减轻高脂血症小鼠的动脉粥样硬化病变发展并抑制腹主动脉瘤形成。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Yang, Guangrui;Zhang, Jiayang;Jiang, Tingting;Monslow, James;Tang, Soon Yew;Todd, Leslie;Puré, Ellen;Chen, Lihong;FitzGerald, Garret A
通讯作者：
FitzGerald, Garret A

Circadian clocks and vascular function.

昼夜节律时钟和血管功能。