Mechanisms regulating autophagy in intestinal epithelial secretory cells

肠上皮是一个不断更新的动态组织。复杂的信号和细胞间通讯通路调节着这一过程。这些不同的途径受生长因子和形态致病因子的控制，如WNT、BMP和Hedgehgs(HH)。其中，HH信号通路调节与组织动态平衡和修复、细胞存活和增殖相关的各种肠道上皮细胞表型。肠上皮细胞表达HH配体，如Sonic Hedgehog(SHH)和India Hedgehog(IHH)。尽管对肠道HH信号有浓厚的兴趣，但对自分泌SHH特异性信号作为肠上皮细胞应激反应的潜在调节因子，如内质网(ER)应激反应及其相关的未折叠蛋白反应(UPR)的参与却知之甚少。这一点特别重要，因为肠上皮分泌细胞，如潘氏细胞和杯状细胞，对内质网应激非常敏感，并依赖适当的UPR来维持体内平衡。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过度激活。持续的内质网应激和UPR反应可能导致细胞凋亡或自噬诱导的分泌功能降低，从而破坏肠道组织的动态平衡。这项研究计划将确定自分泌SHH信号在调节肠上皮细胞对ER应激源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体外3D肠样培养，以评估自分泌SHH信号在来自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性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.