Circadian regulation of physiological functions

SUMMARY: My lab studies circadian-regulated processes and their contributions to health and disease. Circadian regulation refers to daily oscillations in biological functions and is an evolutionarily conserved feature from bacteria to humans. At its core, circadian regulation is governed by a transcriptional negative feedback loop called the circadian clock. Circadian clocks generate 24-hour oscillations in the expression of hundreds of genes in almost every tissue examined and drive the daily oscillation of cellular, tissue-specific, and behavioral functions. Chronic disruption of circadian regulation due to jetlag or night-shift work is associated with multiple defects in innate immunity, metabolism, and sleep. Many disease states are also associated with loss of circadian regulation, including bacterial infection, metabolic diseases, and neurological diseases. Despite the known profound effects of loss of circadian regulation on human physiology, a major gap in knowledge is the identification of circadian-regulated functions that contribute to the pathogenesis of specific diseases. In the last funding period, our MIRA supported the development of tools to enhance or inhibit Drosophila circadian clocks; the investigation of glial function in both Drosophila and mice; and the investigation of a core function for sleep in Drosophila. In the current proposal, we focus on circadian-regulated metabolism, which has emerged as a major theme in our work. We describe two projects involving circadian-regulated metabolism in Drosophila: sensitivity to oxidative stress due to chronic short sleep (Project 1) and metabolic regulation of host tolerance of bacterial infection (Project 2). · Project 1: One of the most obvious manifestations of circadian rhythm is sleep. Sleep, or obligate rest during the 24-hour circadian cycle, is evolutionarily conserved. Yet the physiological function of sleep remains unclear. Our published MIRA-funded results support the hypothesis that a key function of sleep is defense against oxidative stress. Our more recent preliminary data suggest that chronic short sleep causes sensitivity to oxidative stress due to underlying changes in metabolism. We will investigate this in Project 1. · Project 2: There are two types of defense mechanisms against infection: resistance and tolerance. Resistance mechanisms kill pathogens, while tolerance mechanisms limit the pathogenic effects of infection. Tolerance is much less well understood than resistance. In NIGMS-funded research, my lab previously identified a circadian-regulated, TORC2-mediated mechanism of host tolerance against B. cepacia infection. In preliminary data, we found that Sting mutants also have increased tolerance against B. cepacia infection. The Stimulator of Interferon Genes (STING) pathway is a conserved innate immune response and known resistance mechanism. STING also has a second distinct function in both mammals and Drosophila: regulation of lipid metabolism. We will investigate whether STING’s roles in immunity and metabolism intersect during infection in Project 2.