Research Projects

Ancient Greco-Romans recognized the effects of circadian cycles on the severity of inflammatory diseases and prescribed treatments based on the time of day. Today, we understand the underlying basis for these temporal effects on physiological parameters, which are transcription-translation feedback loops (TTFLs) comprising a network of core circadian clock components (mRNA and proteins) that establish cell-autonomous oscillations of approximately 24 hours. These oscillators across various tissues and organs are entrained by external light and dark cycles. As the levels of these core clock components wax and wane in tune with external time, they influence the functioning of various physiological processes by acting as transcription factors or more directly via protein-protein interactions. The "phase" of the circadian clock may affect a multitude of cellular responses, such as the phenomenon of "chronotherapy," which is increasingly important in cancer research. However, clinical trials have had limited success due to heterogeneity in internal time of individuals, which can lead to differences in optimal treatment strategies. The key challenge is to infer the internal body time of an individual, and ideally that of specific tissue types, from a single time point. This is achieved by developing a spatially resolved method to infer circadian phase at the single cell level, using theoretical and computational modeling combined with state-of-the-art multiplexed single molecule fluorescence in situ hybridization (smFISH) techniques.