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：
8961986
负责人：
ALEKSEY V MATVEYENKO
金额：
$ 29.61万
依托单位：
MAYO CLINIC ROCHESTER
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/8961986
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）：由于常见条件（例如睡眠损失和转移工作）引起的昼夜节律的破坏在现代社会中越来越普遍，美国近20％的劳动力在美国暴露于某种类型的轮班工作。暴露于昼夜节律破坏的人增加了2型糖尿病（T2DM）和其他代谢疾病的风险。但是，这种关联的基础机制在很大程度上尚不清楚。胰腺β细胞质量和功能的丧失是一个关键的病理生理事件，导致T2DM中高血糖的发展。因此，当前建议的长期目标是描述负责与昼夜节律干扰有关的个人中β细胞功能和质量丧失的分子机制。为了实现这些目标研究，在特定目标中1将检查慢性暴露于昼夜节律的体内对β细胞分子昼夜节律钟的功能的影响。为了评估胰岛昼夜节律功能，研究人员将使用具有PER-1：荧光素酶基因报告基因的转基因大鼠模型采用生物发光方法，该模型通过加强电荷耦合耦合器件（ICCD）摄像头监测。特定目标2中概述的研究将调查以下假设：β细胞昼夜节律时钟功能损害了细胞防御对氧化应激的反应，从而导致β细胞功能和存活率丧失。最后，在第三个特定目的中，研究将解决以下假设：昼夜节律褪黑激素在调节β细胞功能，生存和对氧化应激的防御反应中的作用不足。因此，β细胞褪黑激素受体信号的激活有可能减轻昼夜节律未对准和氧化应激对T2DM中β细胞的有害影响。综合概述了具体目的将解决与了解昼夜节律系统在调节胰腺β细胞功能和T2DM生存中的作用有关的临床相关翻译问题。