Frontiers in Circadian Medicine

Our lives are intimately linked to Earth’s 24-hour solar cycle via circadian clocks that coordinate physiology and behavior into rhythms that coincide with the day/night cycle. By integrating structural biology, biochemistry, and cell biology, we’ve been working to identify how dedicated clock proteins interact with one another to establish a deeper understanding of the transcription-based feedback loop that underlies circadian rhythms in mammals. Recent insights into the genetic basis of morning lark and night owl behavior have shed light on key molecular steps in the clock that play a particularly powerful role in determining the intrinsic timing of circadian clocks in humans. Some of these recent advances will be discussed to explore the biochemical basis for circadian timekeeping.

The mammalian intestine is colonized with ~100 trillion bacteria (the microbiota) that impact host metabolism and can drive obesity. However, we know almost nothing about the molecular mechanisms used by the microbiota to regulate metabolism and promote obesity. My lab is addressing this question by studying microbiota interactions with the intestinal epithelium. Our work has illuminated two key mechanisms so far. First, we have discovered that the microbiota regulates lipid absorption, storage and obesity in mice through the circadian transcription factor NFIL3 (Wang et al., Science 357, p912-916 [2017]). Second, we have found that the enzyme histone deacetylase 3 (HDAC3) also integrates microbial and circadian signals to regulate intestinal lipid absorption and promote obesity (Kuang et al., Science 365, p 1428–1434 [2019]). Together, these findings provide mechanistic insight into how the intestinal microbiota regulates lipid metabolism and obesity. Our findings also pinpoint key molecular links among the microbiota, the circadian clock, and host metabolism.

Studies in social psychology suggest that compromised sleep is a key factor linking persistent loneliness to adverse health conditions. Though experimental manipulations have been widely applied to studies of the control of sleep in animal models, how normal sleep is perturbed by social isolation is unknown. Our work with Drosophila has shown that chronic social isolation reduces sleep, pointing to the potential usefulness of Drosophila for mechanistic studies of this connection. We have used quantitative behavioral analysis and transcriptome profiling to differentiate acute vs. chronic social isolation brain states. Our studies indicate that chronic social isolation induces an altered metabolic gene expression program and a brain state that signals starvation.

The past several decades has seen an explosion of growth in mechanistic understanding of circadian clocks in several model organisms and in humans. However, translation of that knowledge into actionable medical interventions has been slow to non-existent. Here, I will discuss our efforts to develop circadian medicine in a pediatric hospital. I will talk about our recent progress in understanding the molecular output of the clock in the mouse and humans, including identifying new opportunities for circadian dosing time in improving drug action -- hypothesis-driven, mechanistic circadian medicine. I will talk about our efforts to test these hypotheses prospectively in model organisms and retrospectively in large clinical databases. Finally, I will discuss future opportunities and challenges.

Using mice subjected to a jet lag paradigm we take a multi-omics and behavioral approach to provide evidence that females are more resilient to circadian disruption than males. This is consistent with some prior evidence in the literature from our own work and that of others. This and reflect adaptation to the biological imperative. Although data in humans are largely indirect, interrogation of the UK Biobank provides evidence consistent with this hypothesis. Differences between the sexes must be considered when interrogation circadian biology.

My research program is focused on translating fundamental knowledge about the circadian biology of the cardiovascular system into clinical applications. My laboratory investigates how circadian dysregulation drives heart diseases, including myocardial infarction (heart attack), hypertension (high blood pressure), cardiac hypertrophy, and heart failure – our leading causes of death. We also examine how the heart’s circadian biology can be therapeutically manipulated to benefit how we heal from disease, using transgenic, environmental or pharmacologic approaches to slow or reverse ongoing damage. This pioneering new field of medicine, termed Circadian Medicine, will lead to longer and healthier lives. We have the exciting opportunity as well as the responsibility to improve the lives of people, communities, and the world around us.

Sleep of sufficient duration, continuity, and intensity is necessary to promote high levels of cognitive performance during the wake period and to prevent physiological changes that may predispose individuals to many adverse health outcomes. Long-term shift working schedule and frequent transmeridian travel have become inevitable for many in the current society. These factors lead to the out-of-sync condition of the sleep timing with the internal body clock, and thus significantly contribute to many health conditions that we are facing. In addition, sleep insufficiency is prevalent due to the high demand in work, school, and many environmental factors. Our group uses human genetics approach to identify genes/mutations that give rise to unusual sleep behaviors in human. Mouse models mimicking human condition, coupled with in vitro molecular studies, offer new insight into the underlying mechanisms. Because of the fundamental role that sleep plays in our health, the pathways for regulating sleep are intertwined with those regulating other functions. Thus, our method also offers opportunities to investigate how sleep can impact other conditions, including pain and memory regulations. These genes/mutations have provided unique opportunities to reveal the molecular mechanism of human sleep regulation and beyond.