Grant: Operating Grant

The functional complexity of multicellular organs such as the stomach and intestine involves a high degree of coordination among diverse specialized cell types. Maintaining this organization as well as regulation of gastro-intestinal (GI) cell functions requires a permanent and dynamic crosstalk between epithelial and underlying mesenchyme. This crosstalk is mediated by crucial soluble factors such as the Bone Morphogenetic Proteins (Bmps). Bmp signaling within the GI is complex: Bmps and their receptors are expressed in both epithelial and mesenchymal compartments, suggesting bidirectional signaling between the mesenchyme and the epithelium. The use of genetically modified mice is a powerful tool to establish significant advancement in the understanding of the in vivo function of a molecule of interest, especially in the context of GI epithelial-mesenchymal interactions. Our studies indicate that Bmp signaling pathway in the mesenchyme is more involved in initiating GI pathologies, such as gastric and colorectal cancer as well as IBD, than originally suspected. The main hypothesis for this grant proposal is that loss of mesenchymal BmpR1a receptor and its subsequent intracellular signalization reprogrammed GI activated-fibroblasts into reactive mesenchyme leading to the development of GI diseases. This research proposal will unravel the precise molecular cascade emerging from this important cellular reprograming following the loss Bmp signaling in activated-fibroblasts. Improving our knowledge of this promising pathway in adapting a reactive GI mesenchyme might ultimately contribute to developing cell-based therapies for pathologies such as the inflammatory bowel diseases and GI cancer.