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Research Focus - Hong Laboratory

Fundamental mechanisms of circadian rhythms

Circadian rhythms possess three defining properties: endogenous oscillations, phase shift, and temperature compensation. Molecular mechanisms of circadian rhythms enable autonomous oscillations that persist even in the absence of external time cues, phase shift to realign the phase of the internal clock to external conditions, and maintenance of circadian periodicity within the range of physiological temperature. Recently, we used mathematical modeling to elucidate novel hypotheses regulating the light-dependent phase shift and the period of circadian rhythms. We use Neurospora crassa to experimentally validate molecular mechanisms determining the phase shift and period of circadian rhythms. 

Roles of circadian rhythms in cell cycle and proliferation

Cell cycle and circadian rhythms are coupled despite their distinct functions and circadian clock-gated cell division cycles are observed in various organisms from cyanobacteria to mammals. A few of the molecular connections orchestrating intracellular coupling have been uncovered: e.g. the cell cycle inhibitory kinase, WEE1 and the cyclin-dependent kinase inhibitor p21, are regulated by circadian transcription factors. In addition, core clock proteins, PER1 and PER2, activate cyclin-dependent kinase inhibitor p16 in mouse tissues, and PER1 activates a checkpoint kinase 2 in human cancer cells. And most recently, we discovered that the intestinal epithelial circadian clocks regulate cell cycle in both mouse and human intestinal enteroids, and that intestinal epithelial circadian clocks regulate the timing of cell divisions of intestinal stem and progenitor cells via intercellular WNT signaling. Building on this data, we investigate molecular mechanisms that determine circadian clock-dependent cell proliferation and differentiation using mouse and human enteroids. 

Roles of circadian rhythms in cancer treatments

Over 1 in 4 American workers are shift workers with frequent disruptions in their circadian rhythms and increased risk of GI diseases including colorectal cancer, which is the second leading cause of cancer-related deaths in the U.S.. Circadian rhythms strongly influence cell cycle and proliferation, and play a fundamental role in gastrointestinal physiology. Importantly, disruption of circadian rhythms increases gut permeability, which, in turn, increases risks of infection and translocation of proinflammatory bacterial products (e.g. endotoxins), which may exacerbate metastatic colorectal tumor growth. However, the mechanisms that connect circadian rhythms and tumor development, and chronotherapeutic regimens for cancer treatments remain largely unknown. Based on our previous findings on the link between circadian rhythms and cell proliferations, we seek to systematically characterize remodeling of clock-controlled genes and signaling pathways in colorectal tumors and design novel chronotherapeutic regimens to maximize the efficacy of drugs for cancer cells while minimizing toxicity in normal cells. 

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