The lining of the fly gut sends out stress signals that tell stem cells when to repair damage, and researchers are now unpicking exactly how that conversation works. This matters because human gut tissue is under constant assault from toxins, microbes, and wear-and-tear. When the gut’s ability to sense damage and trigger repair fails, the result can be chronic inflammation, tissue degeneration, or cancer. Despite its importance, the molecular chain of command from a damaged cell to a stem cell remains poorly understood. Using the fruit fly’s powerful genetic toolkit, the team will map three specific stress-response mechanisms: how reactive oxygen molecules from damaged cells spur stem cells into action, how certain stress pathways pulse in daily circadian rhythms to maintain tissue health, and how existing gut cells stretch their lifespan when stem cells are blocked from making replacements. This is fundamental science. There is no immediate clinical application. But understanding how tissues naturally sense injury and coordinate repair could eventually point toward new treatments for inflammatory bowel disease, age-related gut decline, and cancers where these signals go awry.
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Many adult epithelial tissues lose cells from constant environmental stress. Thus, an epithelium’s ability to sense stress, defend itself and stimulate repair (e.g. by stem cells) is vital to prevent tissue dysfunction, degeneration, inflammation and cancer. Despite its importance, this process is poorly understood. Using the adult Drosophila intestine and its unparalleled genetics, combined with proteomics, transcriptomics and fixed and live imaging, I will determine how stress signalling promotes epithelial resilience, maintenance and regeneration focussing on three main aims. 1) Reactive oxygen species (ROS) produced by damaged fly intestinal epithelial cells (IECs) promote intestinal stem cell (ISC)-mediated regeneration, partly via p38 signalling in IECs. I will determine how ROS promote intestinal regeneration by identifying ROS-controlled regulators of regeneration and determining molecular responses to ROS/stress signalling. 2) I have recently found that some stress pathways display rhythmic, circadian activation. I will investigate their role in intestinal maintenance. 3) I have shown that when new IEC production by ISCs is inhibited, IECs increase their lifespan to prolong epithelial maintenance. I will identify adaptive mechanisms that extend IEC lifespan when new cell production is blocked. Understanding these processes could provide novel therapeutic strategies for tissue regeneration, inflammatory diseases, cancer and age-related pathologies.
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