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 现在，Shiftwork被认为是2型糖尿病（T2D）的危险因素；然而这些机制是这些机制 关联知之甚少。解决此知识差距需要融合新陈代谢领域 和年级生物学。 T2D病理生理学的特征是代谢柔韧性受损和昼夜节律 破坏和骨骼肌昼夜节律可能是在这些特征的交点处。代谢灵活性 是有效切换燃料来源的能力，并且在很大程度上由骨骼肌肉维护，而 胰岛素抵抗（IR）暗示代谢不灵活性。同样，骨骼肌时钟干扰原因 临床前模型中的胰岛素抵抗，与人类的葡萄糖耐受性受损有关。 短期夜班的实验模拟引起糖尿病前表型，表明昼夜节律 系统在葡萄糖代谢中起作用。在此，我们将测试真实的夜班工作的假设 会损害代谢灵活性，这将与骨骼肌时钟干扰有关。我们将 进行严格控制的住院研究，以评估和比较全身代谢灵活性 创新的24h代谢室方案，以及骨骼肌时钟基因的昼夜转移 与夜班工人。 NIH K01指导的科学家职业发展奖旨在丰富 候选人的研究和培训经验，导致独立的跨学科研究。 解决了轮班工人中T2D风险的公共卫生问题。候选人将学习经典概念 高级导师的代谢灵活性和时间生物学，并获得深入的培训和动手 尖端方法的经验：全室代谢室，人类骨骼肌细胞培养， 和临床昼夜节律方案。调查团队的独特位置可以解决轮班工作之间的联系， 代谢僵硬和骨骼肌时钟。 Adventhealth的转化研究所（赞助） 机构）设有一个为生物循环收集准备的临床研究部门，这是4个最先进的代谢 室内西装和湿的实验室空间，专门用于人类骨骼肌细胞培养工作。这个项目是 与Adventhealth的护理，全人和学术研究小组的合作努力，他们将 通过直接到达约1,500名当地护士工作夜班来支持招募。这些研究会 通过识别特定于转移工作的代谢缺陷，有可能改变范式 针对胰岛素抵抗和代谢的脂肪酸氧化成分受损的干预措施 在24小时夜间周期中的灵活性。在资金期结束时，候选人将很好 配备了R级资助。运动/体育锻炼干预措施很可能减轻或 防止与转移工作相关的代谢功能障碍将是未来方向上的主要重点。我们完全期望 该建议将在调查团队中启动一系列产品合作，这将 最终最终达到了针对慢性代谢疾病伯恩（Burnen）的大量工作。