Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

昼夜节律失调在 2 型糖尿病 β 细胞衰竭中的作用

基本信息

批准号：
8478529
负责人：
ALEKSEY V MATVEYENKO
金额：
$ 33.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8478529
关键词：
Address American Apoptosis Attenuated Beta Cell Bioluminescence Cell Survival Cell physiology Chronic Circadian Rhythms Cues Development Diabetes Mellitus Diagnosis Diet Event Exposure to Failure Fatty acid glycerol esters Feedback Functional disorder Gene Expression Profile Gene Proteins Genes Genetic Transcription Goals Hormonal Hormones Hour Human Hyperglycemia Hypothalamic structure Impaired fasting glycaemia Individual Insulin Life Light Link Luc Gene Mammals Mediating Melatonin Melatonin Receptors Metabolic Diseases Modeling Molecular Monitor Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Organism Oxidative Stress Patients Peripheral Phase Photoperiod Physiological Pilot Projects Pineal gland Play Population Predisposition Property Rattus Receptor Signaling Receptor, Melatonin, MT2 Regulation Reporter Research Personnel Risk Risk Factors Role Simulate Sleep Societies Structure of beta Cell of islet System Testing Therapeutic Transcriptional Regulation Transgenic Organisms Translations United States body system charge coupled device camera circadian pacemaker clinically relevant defense response design diabetes risk disorder prevention experience gene induction genome wide association study in vivo insight insulin secretion islet islet amyloid polypeptide overexpression public health relevance response shift work suprachiasmatic nucleus therapy development

项目摘要

DESCRIPTION (provided by applicant): Disruption of circadian rhythms due to common conditions such as sleep loss and shift work are becoming increasingly prevalent in modern societies with nearly 20% of the workforce in the United States exposed to some type of shift work. Individuals exposed to circadian disruption have increased risk for development of Type 2 diabetes (T2DM) and other metabolic diseases. However, the mechanisms underlying this association are still largely unknown. The loss of pancreatic beta-cell mass and function is a critical pathophysiological event precipitating development of hyperglycemia in T2DM. Thus, the long-term objectives of the current proposal are to delineate molecular mechanisms responsible for the loss of beta-cell function and mass in individuals exposed to conditions associated with circadian rhythm disruptions. To achieve these objectives studies in Specific Aim 1 will examine effects of chronic exposure to circadian misalignment in-vivo on the function of the beta-cell molecular circadian clock. To assess islet circadian clock function investigators will employ bioluminescence approach using a transgenic rat model with Per-1: luciferase gene reporter monitored by intensified charge-coupled device (ICCD) camera. Studies outlined in Specific Aim 2 will investigate the hypothesis that disrupted beta-cell circadian clock function compromises cellular defense response to oxidative stress resulting in the loss of beta-cell function and survival. Lastly, in the third Specific Aim, studies will address the hypothesis that circadian hormone melatonin plays a previously underappreciated role in the regulation of beta cell function, survival and defense response to oxidative stress. Thus, the activation of beta- cell melatonin receptor signaling has the potential to attenuate deleterious effects of circadian misalignment and oxidative stress on the beta-cell in T2DM. Taken together outlined specific aims will address a clinically relevant translation question related to understanding the role of the circadian system in regulation of pancreatic beta-cell function and survival in T2DM.

描述（由申请人提供）：由于睡眠不足和轮班工作等常见情况而导致的昼夜节律紊乱在现代社会中变得越来越普遍，美国近 20% 的劳动力面临某种类型的轮班工作。昼夜节律紊乱的个体患 2 型糖尿病 (T2DM) 和其他代谢疾病的风险增加。然而，这种关联背后的机制仍然很大程度上未知。胰腺β细胞质量和功能的丧失是促进T2DM高血糖发生的关键病理生理学事件。因此，当前提案的长期目标是描绘导致暴露于昼夜节律紊乱相关条件的个体中β细胞功能和质量丧失的分子机制。为了实现这些目标，具体目标 1 中的研究将检查体内长期暴露于昼夜节律失调对 β 细胞分子昼夜节律钟功能的影响。为了评估胰岛生物钟功能，研究人员将采用生物发光方法，使用转基因大鼠模型，并通过增强电荷耦合器件 (ICCD) 摄像头监测 Per-1：荧光素酶基因报告基因。具体目标 2 中概述的研究将调查以下假设：β 细胞生物钟功能被破坏会损害细胞对氧化应激的防御反应，从而导致 β 细胞功能和存活的丧失。最后，在第三个具体目标中，研究将解决这样的假设：昼夜节律激素褪黑激素在调节 β 细胞功能、生存和对氧化应激的防御反应中发挥着先前未被充分认识的作用。因此，β细胞褪黑激素受体信号传导的激活有可能减弱昼夜节律失调和氧化应激对T2DM中β细胞的有害影响。总而言之，概述的具体目标将解决与理解昼夜节律系统在调节 T2DM 胰腺 β 细胞功能和生存中的作用相关的临床相关翻译问题。