Shift workers comprise nearly 20% of the US working population, and exhibit disparately high rates of several cancers, obesity, diabetes, stroke, and circulatory disease. A better understanding of the mechanistic factors contributing to increased morbidity in shift workers is needed before the risks associated with these work schedules can be reduced. Simulated rotating shift work in mice, termed Environmental Circadian Disruption (ECD), leads to sleep loss, accelerates death, and dysregulates innate immune function. ECD-exposed mice exhibit pathologically severe inflammatory responses to bacterial endotoxin and increased infarct size following ischemic stroke. Our preliminary work has helped us establish a hypothesis that ECD disrupts the immune cell molecular circadian clock and produces a novel form of immunosuppression. We posit that this immunosuppression specifically slows anti-inflammatory signaling during an inflammatory challenge due to loss of adequate signaling through the TAM family of receptor tyrosine kinases, resulting in uncontrolled pro- inflammatory cytokine release and pathology. In this grant we will investigate the mechanistic underpinnings of the immunological consequences of ECD using newly developed in vitro ECD paradigms, laying the groundwork for translation of our work to human subjects exposed to laboratory-simulated and real-world shift work. The long term goal of this research effort is to develop screening tools and preventative medical treatments that may mitigate the adverse health consequences associated with work schedules that cause circadian disruption.
Chronic disruption of circadian timing and sleep through altered lighting environments, as experienced during shift work, can have severe health consequences via effects on the immune system. This project will investigate the mechanisms of immune dysfunction that arise during circadian disruption in order to identify strategies to reduce the adverse health consequences of these schedules.
|Liu, Dong; Stowie, Adam; de Zavalia, Nuria et al. (2018) mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction. Proc Natl Acad Sci U S A 115:E3296-E3304|
|Baba, Kenkichi; Davidson, Alec J; Tosini, Gianluca (2015) Melatonin Entrains PER2::LUC Bioluminescence Circadian Rhythm in the Mouse Cornea. Invest Ophthalmol Vis Sci 56:4753-8|
|Evans, Jennifer A; Suen, Ting-Chung; Callif, Ben L et al. (2015) Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body. BMC Biol 13:43|
|Evans, Jennifer A; Leise, Tanya L; Castanon-Cervantes, Oscar et al. (2015) Neural correlates of individual differences in circadian behaviour. Proc Biol Sci 282:|