The Role of Autophagy in Intestinal Regeneration

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Project Summary/Abstract The main goal of these studies is to discover novel ways to prevent chemotherapy-related intestinal injury. Dox- orubicin is a chemotherapy drug administered to treat metastatic cancers in patients and is commonly used to model intestinal injury in mice. Chemotherapy has many off target side effects, including the inflammation of mucus membranes termed mucositis. Patients commonly present with pain, vomiting and diarrhea causing high morbidity. Worsening symptoms reduce patient adherence to treatment and limit physician administration of therapeutic chemotherapy doses. There are no effective therapies to attenuate mucositis, and despite the need, there is limited research on intestinal mucositis. Intestinal stem cell (ISC) damage is a common feature of murine intestinal mucosal damage by various insults. Pathways related to the regenerative process of the intestine in- clude those that drive cellular remodeling, such as autophagy. Fasting prior to doxorubicin chemotherapy ad- ministration in mice has been shown to protect intestinal stem cells from DNA damage by activating autophagy. Furthermore, terminally differentiated Paneth cells (PCs) are resistant to injury and can de-differentiate to help reestablish the integrity of the intestinal epithelium. While the early cellular reconstructive mechanisms that allow post-mitotic PCs to revert to an ISC state are relatively unknown, insights can be extrapolated from the acquired plasticity of other terminally differentiated cell types. Notably, the early activation of autophagy is an essential step in the reprograming of terminally differentiated fibroblasts into pluripotent stem cells invitro. These findings highlight the importance of autophagy in the protection from injury, and the recovery from injury when protection is not possible. Aim 1 of this proposal will elucidate the role of autophagy in the protection against doxorubicin-induced intestinal mucosal damage. First, rapamycin, an autophagy inducing drug, will be administered to mice to determine if the protective effects of fasting can be emulated by the stimulation of au- tophagy alone. To enhance the translatability of these findings the effect of fasting/autophagy on intestinal injury and tumor responsiveness will be examined in a doxorubicin-sensitive metastatic cancer model. Aim 2 will ex- amine the role of autophagy in PC-mediated intestinal regeneration following injury. Two PC-specific genetically modified mouse models will be generated to determine if autophagy is required for PC-mediated intestinal re- generation. The long-term goal of this project is to produce generalizable breakthroughs that have broader im- plications for the gamut of GI medical conditions that result from epithelial damage. All experiments will be conducted at Baylor College of Medicine, with the assistance of numerous core facilities with state-of-the-art equipment and technology. This project is strong vehicle for physician scientist training and will foster profi- ciency in technique, critical thinking, communication and mentorship.