FlyGutHomeostasis SIGNED

Project "FlyGutHomeostasis" data sheet

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 Project objective

Due to its remarkable self-renewing capacity, the fly gut has recently become a prime paradigm for studying stem-cell function during adult tissue homeostasis. This capacity for self-renewal relays on the proliferative activity of the intestinal stem cells (ISC), which is tightly coupled with cell loss to maintain intestinal homeostasis. ISC proliferation is controlled by multiple local and systemic signals released from the ISC niche (enterocytes (ECs), enteroendocrine (EE) cells, enteroblasts (EBs), and visceral muscles (VMs)) and non-gastrointestinal (non-GI) organs. Despite the physiological divergence between insects and mammals, studies have shown that flies represent a model that is well suited for studying stem cell physiology during ageing, stress, and infection. As a saturating approach to identify local and systemic signals controlling intestinal homeostasis in steady-state and challenged conditions, RNAis will be used to known down all genes encoding secreted peptides specifically in ECs, EEs, or VMs and all genes encoding transmembrane and membrane-associated proteins in the VMs. The proposed screens should identify novel intra- and inter-organ circuitries allowing communication between the gut and other organs to provide organismal health. In addition, the systematic knockdown of secreted peptides from the ISC niche could identify gut-derived signals that couple changes in environmental inputs, such as nutrient availability, with systemic changes in feeding behavior, energy balance, and metabolism. Since large-scale approaches are not feasible in vertebrate models, the signals identified in the above screens could potentially reveal novel couplings contributing to mammalian GI homeostasis and disease. The final part of the proposed project aims a deciphering the molecular signals coupling epithelial fitness with ligand-independent TNFR activation to control ISC division and epithelial turnover in steady-state, challenged and pathological conditions.