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Circadian rhythms are oscillations in various physiological processes that occur with a 24hhrs period. These rhythms serve as an anticipatory mechanism and thus enhance survival of organisms in the face of an ever changing environment. While traditionally circadian rhythms were supposed to emanate from the suprachiasmatic nuclei (hypothalamus) is now known that individual organs and cell have their own autonomous clock. At the molecular level, circadian rhythms re generated by rhythmic oscillations in the transcription and translation of core "clock" genes. The lung transcriptome shows robust circadian oscillations. Further symptoms and response to therapy in many disease states of the lung exhibit distinct circadian rhythms. At present, our understanding of the clock regulation of lung function rests heavily, though not exclusively, upon the response of lungs to lipopolysaccharide (LPS). Exposure of the lungs to LPS induces a very short-lived, predominantly neutrophilic inflammation that resolves completely without significantly altering the lung architecture. Thus, this model fails to capture the circadian regulation of the host response in conditions where the pathogen mediates damage through repetitive cycles of replication in the lung or where there is significant tissue remodeling.
We have overcome this major limitation by working with a murine model of influenza A virus (IAV) and standardizing it for the study of circadian regulation of lung injury and inflammation. A hallmark of circadian regulation is a difference in outcomes based on time of day at which the initial insult was sustained.
The lab's published data demonstrates that clock control of lung injury is mediated by limiting pathology (less inflammation and better repair on histology) and not by reducing viral burden. Their preliminary data reveals that Bmal1 deletion in lung epithelial sub-populations involved in repair (AT2 cell, Sox2+ basal cells and Scgb1a1club cells) all have reduced regenerative capacity in organoid assays.
The lab team also observed that the disruption of the clock specifically in (Scgb1a1+) club cells or depletion of NK cells abolishes the diurnal variability in response to IAV and results in higher mortality. Work in the Sengupta lab focuses on the mechanistic basis of these observations.