Multiscale Analysis of Inter-Clock Communication

时钟间通信的多尺度分析

• 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
• 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

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）： 昼夜节律时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开发了振荡器功能的脚手架模型，其中下丘脑的上核核具有“主钟”，并在大多数主要的器官系统中策划了外围振荡器。这些中央和外围振荡器系统产生了一系列昼夜节律级联，最终在观察到的生理和行为振荡中最终导致。该组织在动物模型中的遗传破坏会导致病理生理后果，例如葡萄糖不耐症和胰岛素抵抗，这是患有心血管疾病的高风险的代谢综合征的成分。我们提供了令人信服的证据，表明时钟之间的沟通更加复杂，并且可能涉及外围到外围和外围钟到中时钟的通信。在这里，我们测试了一个中心假设，即外围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有条件小鼠模型，其中删除了振荡器的必需组件BMAL1，我们将使用生理和系统方法来测试振荡器在内皮细胞中功能的假设调节血管平滑肌功能（和vice vice vice and vice vice），并影响血压的炎症变化，并影响血压，肿胀，肿瘤生成和loceasosis和locesos和locesos Aimors（特定于Aimotor Aimors 1）。我们还将检验以下假设：脂肪细胞中的振荡器功能调节巨噬细胞功能（反之亦然），影响葡萄糖稳态，对炎性刺激的反应和喂养节律（特定目标2）。此外，我们提出了一个机械假说，即细胞类型特异性振荡器功能的破坏会导致附近细胞的振荡器异常，并且这种干扰传播到肝，肾上腺，肾脏和大脑（特定的目标3）。最后，使用系统方法，我们将检查通过特定细胞类型中振荡器功能的遗传破坏引起的网络级别变化，并开始探测网络以网络输送昼夜节目信息以及识别候选信号分子（特定目标4）。 （抽象的结尾）