ABSTRACT Impaired intestinal epithelial healing can contribute to chronic inflammation in inflammatory bowel disease (IBD). Current IBD therapies target the immune response without addressing intestinal epithelial repair defects, which may contribute to risk of relapse in patients with IBD. Studying intestinal epithelial repair will lead to a better understanding of IBD pathogenesis as well as novel therapies that may be more effective than current therapies. Intestinal epithelial homeostasis is maintained by adult stem cells that reside at the base of the crypt. When these stem cells are injured or depleted, other differentiated cells in the epithelium, specifically secretory cells, can de-differentiate and replenish the epithelium. A specific secretory cell type, Paneth cells, are found at the base of the crypt intercalated between the stem cells, putting them in a prime location to replace stem cells when they are ablated. However, mechanisms of Paneth cell plasticity are unknown. Our lab recently showed that cells with high autophagic vesicle content were identified as having stem-like capacity via their ability to generate organoids after being seeded as single cells. These findings and other studies showing that autophagy is necessary for the intestinal epithelium to recover after injury, suggest that autophagy may play an important role in this de-differentiation process. Additionally, recent studies have shown that after injury, the intestinal epithelium upregulates fetal-like reversion genes and no longer expresses differentiated cell genes, suggesting a reversion to a more plastic and undifferentiated state. Though both autophagy and fetal-like reversion have been suggested to be mechanisms for de-differentiation, it is not clear whether these two processes are related. Therefore, I hypothesize that Paneth cells require autophagy to transition through a fetal-like state to de- differentiate following epithelial tissue injury. In Aim 1, I will determine if autophagy is necessary for Paneth cells to de-differentiate. In Aim 2, I will test whether the increase in organoid formation from Paneth cells with high autophagic vesicle content is due to an increased ability to upregulate fetal-like reversion genes through YAP signaling. These aims will define a role for autophagy in Paneth cell plasticity and whether expression of fetal-like reversion genes contribute to this process. This work will provide a basis for understanding why patients with IBD have impaired epithelial healing and may lead to novel therapeutics focusing on epithelial cell autophagy.