Thursday, December 26, 2024
12/26/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).