Mechanisms regulating autophagy in intestinal epithelial secretory cells

肠上皮是一个不断更新的动态组织。复杂的信号传导和细胞间通讯途径调节这一过程。这些不同的途径由生长因子和形态发生素控制，如WNT、BMP和Hedgehogs（HH）。其中，HH信号通路调节与组织稳态和修复、细胞存活和增殖相关的各种肠上皮细胞表型。肠上皮细胞表达HH配体，例如Sonic hedgehog（SHH）和Indian hedgehog（IHH）。尽管对肠道HH信号传导有强烈的兴趣，但对自分泌SHH特异性信号传导作为肠上皮细胞应激反应（例如内质网（ER）应激反应及其相关的未折叠蛋白反应（UPR））的潜在调节剂的参与知之甚少。这是特别重要的，因为肠上皮分泌细胞，如潘氏细胞和杯状细胞，对ER应激非常敏感，并依赖于适当的UPR来维持稳态。此外，遗传和环境因素可能导致细胞应激，导致肠上皮内未折叠蛋白水平增加和UPR过度活化。持续的ER应激和UPR反应可能导致分泌功能降低，作为细胞凋亡或自噬诱导的结果，从而破坏肠组织的稳态。本研究计划将确定自分泌SHH信号在调节肠上皮细胞对ER应激的特异性反应中所起的特定作用。我们将使用转基因小鼠模型来产生离体3D肠样培养物，以评估自分泌SHH信号在分泌谱系的肠上皮细胞中的作用。我们希望这些策略将提供关于上皮SHH信号级联的性质的关键信息，作为调节肠道ER应激和UPR的重要途径。

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.**