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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK106562-01A1
Application #
9242127
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2017-07-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Kasendra, Magdalena; Tovaglieri, Alessio; Sontheimer-Phelps, Alexandra et al. (2018) Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids. Sci Rep 8:2871
Richmond, Camilla A; Rickner, Hannah; Shah, Manasvi S et al. (2018) JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation. Stem Cell Reports 10:17-26