Mechanisms regulating autophagy in intestinal epithelial secretory cells

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The intestinal epithelium is a dynamic tissue continuously renewed. Complex signaling and intercellular communication pathways regulate this process. These various pathways are controlled by growth factors and morphogens, such as WNT, BMP and Hedgehogs (HH). Of these, the HH signaling pathway regulates various intestinal epithelial cell phenotypes associated with tissue homeostasis and repair, cell survival and proliferation. Intestinal epithelial cells express HH ligands, such as Sonic hedgehog (SHH) and Indian hedgehog (IHH). Despite the strong interest in gut HH signaling, little is known of the involvement of autocrine SHH-specific signaling as a potential regulator of intestinal epithelial cell stress responses, such as the endoplasmic reticulum (ER) stress response, and its associated unfolded protein response (UPR). This is of particular importance since intestinal epithelial secretory cells, such as Paneth and goblet cells, are very sensitive to ER stress and depend on proper UPR for homeostasis. In addition, genetic and environmental factors may cause cellular stresses leading to increased unfolded protein levels and excessive UPR activation within the intestinal epithelium. A sustained ER stress and UPR response may lead to reduced secretory functions, as a consequence of cellular apoptosis or autophagy induction, thereby disrupting intestinal tissue homeostasis. This research program will establish the specific roles played by autocrine SHH signaling in the regulation of the intestinal epithelial cell specific response to ER stressors. We will use a genetically modified mouse model to generate ex vivo 3D enteroid cultures to assess the role of autocrine SHH signaling in intestinal epithelial cells from the secretory lineage. It is our hope that these strategies will provide crucial information on the nature of the epithelial SHH signaling cascade as an essential pathway regulating intestinal ER stress and UPR.