Multiscale Analysis of Inter-Clock Communication

时钟间通信的多尺度分析

基本信息

批准号：
8102921
负责人：
GARRET A FITZGERALD
金额：
$ 50.23万
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/8102921
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

DESCRIPTION (provided by applicant): 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). (End of Abstract)

描述（由申请人提供）：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。过去十年的研究已经发展了振荡器功能的支架模型，其中下丘脑的视交叉上核拥有“主时钟”并协调大多数主要器官系统中存在的外周振荡器。这些中枢和外周振荡系统产生一系列昼夜节律转录节律，最终导致观察到的生理和行为振荡。在动物模型中，该组织的遗传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，这是心血管疾病高危人群中常见的代谢综合征的组成部分。我们提出了令人信服的证据，表明时钟之间的通信更加复杂，并且可能涉及外设到外设和外设到中央时钟通信。在这里，我们测试了中心假设，即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。使用细胞类型特定的条件小鼠模型，其中 Bmal1（振荡器的必需成分）被删除，我们将使用生理学和系统方法来检验内皮细胞中的振荡器功能调节血管平滑肌功能（反之亦然）并影响的假设血压、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（反之亦然）并影响葡萄糖稳态、对炎症刺激的反应和进食节律的假设（具体目标 2）。此外，我们建议测试一种机制假设，即细胞类型特异性的振荡器功能破坏会导致附近细胞的振荡器异常，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，我们将使用系统方法检查特定细胞类型中振荡器功能的遗传破坏引起的网络水平变化，并开始探测昼夜节律信息的网络到网络的传递以及识别候选信号分子（具体目标 4）。（摘要完）