Functionally distinct populations of murine intestinal stem cells (ISCs), including rapidly cycling crypt base columnar (CBC) ISCs and dormant ISCs (d-ISCs), maintain the highly self-renewing intestinal epithelium. While CBC ISCs play an important role in daily homeostasis, d-ISCs are highly resistant to injury and play an important role during intestinal regeneration. Precisely what cellular and molecular mechanisms regulate the regenerative response of d-ISCs remains largely unknown. Regulated by complex and still poorly understood mechanisms, fasting triggers intestinal injury from which the intestine recovers during re-feeding mediated by d-ISCs. Fasting/re-feeding is therefore a useful tool to study the mechanisms that regulate the d-ISC response to injury. We recently showed that fasting leads to a dramatic induction in d-ISC number and regenerative response, associated with a transient inactivation of PTEN, a negative regulator of the PI3KAKTmTORC1 pathway. In contrast, permanent deletion of PTEN led to a complete loss of d-ISCs, due in part to unrestrained PI3K signaling. This phenotype could be rescued by inhibition of PI3K signaling and increases in canonical Wnt/?catenin (cWnt) signaling. Exactly what downstream effectors of PI3K and cWnt signaling regulate the d-ISC regenerative response remains unclear. Given these findings, this proposal will: 1) establish the role of PI3KAKTmTORC1 signaling in the d-ISC injury response, 2) define the role of cWnt signaling in d-ISC survival/maintenance following PTEN loss, and 3) identify downstream effectors of PI3K and cWnt signaling pathways that regulate the d-ISC regenerative response to injury.
The goal of this project is to better understand how reserve intestinal stem cells help the intestine recover from injury using fasting as an injury model. Identifying the mechanisms that control these cells will provide unique insight into the regulation of intestinal growth, regeneration, and adaptation to the always-changing gut environment. These findings may provide new understanding of early response pathways and possible drug targets for the prevention and treatment of intestinal diseases such as cancer, inflammatory bowel disease, short gut syndrome, and malnutrition.
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