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

描述（由申请人提供）：在现代社会中，由于睡眠不足和轮班工作等常见情况导致的昼夜节律紊乱越来越普遍，美国近20%的劳动力暴露于某种类型的轮班工作。暴露于昼夜节律紊乱的个体患2型糖尿病（T2 DM）和其他代谢疾病的风险增加。然而，这种关联的机制在很大程度上仍然未知。胰腺β细胞质量和功能的丧失是促使T2 DM发生高血糖症的关键病理生理事件。因此，本提案的长期目标是描述暴露于与昼夜节律中断相关的条件的个体中β细胞功能和质量损失的分子机制。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，通过增强型电荷耦合器件（ICCD）相机监测Per-1：荧光素酶基因报告基因。具体目标2中概述的研究将研究以下假设：β细胞生物钟功能受损会损害细胞对氧化应激的防御反应，导致β细胞功能和存活丧失。最后，在第三个具体目标中，研究将解决以下假设：昼夜节律激素褪黑激素在调节β细胞功能、存活和对氧化应激的防御反应中起着以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具有减弱昼夜节律失调和氧化应激对T2 DM中β细胞的有害影响的潜力。总之，概述的具体目标将解决与理解昼夜节律系统在T2 DM中调节胰腺β细胞功能和存活率的作用相关的临床相关翻译问题。

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.