Impact of Shiftwork on Metabolic Flexibility and Skeletal Muscle Clocks

轮班工作对代谢灵活性和骨骼肌时钟的影响

• 批准号: 10572845
• 负责人: Melissa Erickson
• 金额: $ 15.88万
• 依托单位: ADVENTHEALTH ORLANDO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-23 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572845
• 关键词: ARNTL gene; Address; Affect; Biopsy; Cell Culture Techniques; Chronic; Chronobiology; Circadian Dysregulation; Clinical; Clinical Research; Collaborations; Collection; Data; Dedications; Defect; Development; Discipline of Nursing; Exercise; Fasting; Functional disorder; Funding; Future; Genes; Glucose; Glucose Intolerance; Human; Impairment; In Vitro; Individual; Inpatients; Institution; Insulin Resistance; Intervention; K-Series Research Career Programs; Knowledge; Learning; Link; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methodology; Molecular; Muscle Fibers; Muscle satellite cell; Non-Insulin-Dependent Diabetes Mellitus; Nurses; Organelles; Outcome; Participant; Persons; Phenotype; Positioning Attribute; Pre-Clinical Model; Prediabetes syndrome; Productivity; Protocols documentation; Public Health; Research; Research Institute; Risk Factors; Role; Scientist; Series; Skeletal Muscle; Sleep; Small Interfering RNA; Source; Standardization; System; Techniques; Testing; Training; Translational Research; United States National Institutes of Health; Work; blood glucose regulation; burden of illness; circadian; circadian biology; circadian pacemaker; clinical investigation; cohort; design; diabetes risk; exercise intervention; experience; experimental study; fatty acid oxidation; feeding; flexibility; glucose metabolism; impaired glucose tolerance; innovation; molecular clock; oxidation; prevent; recruit; response; shift work; simulation

PROJECT SUMMARY Shiftwork is now recognized as a risk factor for type 2 diabetes (T2D); yet the mechanisms underlying these associations are poorly understood. Addressing this knowledge gap requires converging the fields of metabolism and chronobiology. T2D pathophysiology is characterized by both impaired metabolic flexibility and circadian disruption, and skeletal muscle circadian clocks may be at the intersection of these features. Metabolic flexibility is the capacity to efficiently switch between fuel sources and is largely maintained by skeletal muscle, whereas metabolic inflexibility is implicated in insulin resistance (IR). Similarly, skeletal muscle clock disruption causes insulin resistance in pre-clinical models and is associated with impaired glucose tolerance in humans. Experimental simulations of short-term nightshift induce a prediabetic phenotype, indicating that the circadian system plays a role in glucose metabolism. Herein, we will test the hypothesis that real-world nightshift work impairs metabolic flexibility, and that this will be associated with disrupted skeletal muscle clocks. We will conduct rigorously controlled in-patient studies to assess and compare whole-body metabolic flexibility using innovative 24h metabolic chamber protocols, as well as diurnal shifts in skeletal muscle clock genes in dayshift vs. nightshift workers. This NIH K01 Mentored Scientist Career Development Award was designed to enrich the candidate’s research and training experiences, leading to an independent transdisciplinary research niche that addresses the public health concerns of T2D risk in shift workers. The candidate will learn classic concepts in metabolic flexibility and chronobiology from senior-level mentors and gain intensive training and hands-on experience in cutting-edge methodologies: whole-room metabolic chambers, human skeletal muscle cell culture, and clinical circadian protocols. The investigative team is uniquely positioned to address links between shiftwork, metabolic inflexibility, and skeletal muscle clocks. AdventHealth’s Translational Research Institute (sponsoring institution) houses a clinical research unit prepared for biospecimen collections, 4 state-of-the-art metabolic chamber suits, and wet lab space dedicated to human skeletal muscle cell culture work. This project is a collaborative effort with AdventHealth’s Nursing, Whole-Person, and Academic Research Group, who will support recruitment through directly reaching ~1,500 local nurses working nightshift. These studies will potentially shift the paradigm by identifying a metabolic defect specific to shiftwork that could be modified by interventions targeting both insulin resistance and impaired fatty acid oxidation components of metabolic flexibility across the 24h day-night cycle. At the conclusion of the funding period, the candidate will be well equipped to pursue R-level funding. It is highly likely that exercise/physical activity interventions to mitigate or prevent shiftwork-associated metabolic dysfunction will be a major focus in future directions. We fully expect that this proposal will initiate a long line of productive collaborations among the investigative team, which will eventually culminate in a significant body of work addressing the chronic metabolic disease burden of shiftwork.

项目摘要 轮班工作现在被认为是2型糖尿病（T2 D）的危险因素;然而，这些潜在的机制 人们对协会了解甚少。解决这一知识差距需要融合代谢领域 和时间生物学T2 D病理生理学的特征在于代谢灵活性和昼夜节律受损 中断，骨骼肌生物钟可能处于这些特征的交叉点。代谢灵活性 是在燃料源之间有效切换的能力，主要由骨骼肌维持，而 代谢稳定性与胰岛素抵抗（IR）有关。类似地，骨骼肌生物钟中断导致 在临床前模型中，胰岛素抵抗与人体葡萄糖耐量受损有关。 短期夜班的实验模拟诱导糖尿病前期表型，表明昼夜节律 系统在葡萄糖代谢中起作用。在这里，我们将测试假设，现实世界的夜班工作， 损害代谢的灵活性，这将与破坏骨骼肌时钟。我们将 进行严格控制的住院患者研究，以评估和比较全身代谢的灵活性， 创新的24小时代谢室方案，以及骨骼肌时钟基因在白天的昼夜变化 vs.夜班工人这个NIH K 01指导科学家职业发展奖旨在丰富 候选人的研究和培训经验，导致一个独立的跨学科研究利基， 解决了轮班工人中T2 D风险的公共卫生问题。候选人将学习经典的概念， 从高级导师那里学习代谢灵活性和时间生物学，并获得强化培训和实践 在尖端方法学方面的经验：全室代谢室，人类骨骼肌细胞培养， 和临床昼夜节律协议。调查小组处于独特的地位，以解决轮班工作之间的联系， 代谢能力和骨骼肌生物钟。AdventHealth的转化研究所（赞助 机构）设有一个临床研究单位，为生物标本收集做好准备，4个最先进的代谢 室服和湿实验室空间致力于人类骨骼肌细胞培养工作。这个项目是一个 与AdventHealth的护理，全人和学术研究小组合作，他们将 通过直接接触约1 500名夜班当地护士，支持征聘工作。这些研究将 通过识别特定于轮班工作的代谢缺陷，可能改变范式， 针对胰岛素抵抗和代谢产物中受损脂肪酸氧化成分的干预措施 24小时昼夜循环的灵活性。在资助期结束时，候选人将 有能力获得R级融资。运动/体力活动干预很可能会减轻或 预防轮班相关的代谢功能障碍将是未来方向的主要焦点。我们完全希望 这一建议将在调查小组之间开展一系列富有成效的合作， 最终在一个重要的工作机构解决慢性代谢疾病的轮班工作的负担达到高潮。