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Our long-term goal is to utilize temporal information from the circadian clock and its connections with other cellular processes (e.g. cell cycle, metabolism, etc.) to improve human health. Circadian rhythms are periodic physiological events that recur about every 24 hours. Disruption of circadian rhythms exacerbate progression of numerous diseases ranging from metabolic disorders to cancer. Despite the critical importance of circadian rhythms in human disease progression and treatments, roles of circadian rhythms in complex human diseases remain largely unknown. To achieve our goal, we seek to understand molecular mechanisms of circadian rhythms and their interconnected network with other cellular processes such as cell cycle, DNA damage response, and metabolism in order to design novel therapeutic regimens. These complex biological modules are intertwined by molecular components that communicate and adapt to various external environments to optimize the survival of an organism. We employ mathematical modeling to navigate complex dynamics of molecular networks, and use genetics and molecular biology to validate model-driven hypotheses.
We use different systems from model filamentous fungi, Neurospora crassa, to patient-derived 3-dimensional organoids depending on research questions. Neurospora crassa is one of the pioneering model organisms uncovering fundamental mechanisms of circadian rhythms and provides excellent tools for uncovering fundamental mechanisms of circadian rhythms. Organoids are 3-dimensional multicellular tissue cultures derived from tissues that mimic numerous aspects of an organ including in vivo tissue architecture, multiple cell types and function. In the past decade, we have been performing pioneering work characterizing the existence and function of circadian rhythms in mouse and human enteroids (i.e. organoids derived from the small intestine). We demonstrated that both mouse and human enteroids possess robust circadian rhythms controlling rhythmic expression of 3-10% of transcripts. These rhythmic genes subsequently control the timing of cell divisions and circadian time-dependent responses to pathogens. We aim to uncover how these regulations are disrupted in disease states and utilize such information to design novel therapeutic regimens.
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