There is emerging evidence that distinct populations of actively cycling and quiescent intestinal stem cells (ISCs) co-exist within the small intestine epithelium and function cooperatively in tissue renewal. This proposal explores the hypothesis that these ISC populations are regulated by distinct sets of extracellular signals involved in organ size control and oxygen-sensing. This hypothesis is evaluated by three Specific Aims: (1) to explore the Hippo signaling pathway, implicated in controlling organ size, in regulating the regenerative responses of active and quiescent ISC populations, (2) to examine metabolic regulation of active and quiescent ISCs by the oxygen-sensing pathway, and (3) to determine the molecular signatures of active versus quiescent ISCs by comparative gene expression profiling.
These Specific Aims will be achieved by employing rigorous mouse genetics to examine ISCs in vivo within their stem cell niches and validated ex vivo clonogenic culture techniques that allow for sustained proliferation and multi-lineage differentiation of single isolated ISCs. Achievement of these Aims should provide insight into the molecular differences between active and quiescent ISCs at the transcriptional level and their differential regulation by diverse pathways governing organ size and metabolism.

Public Health Relevance

The intestinal epithelium undergoes rapid and continuous renewal supported by intestinal stem cells and serves as a model tissue to study stem cell biology. Our proposal aims to understand the regulation of distinct populations of intestinal stem cells that are actively proliferating versus dormant. An improved understanding of the stem cell populations and their regulation may lead to new approaches to regeneration of intestine for therapy of intestinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK096048-03
Application #
8725145
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$143,446
Indirect Cost
$10,626
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Barry, Evan R; Morikawa, Teppei; Butler, Brian L et al. (2013) Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493:106-10
Lim, Xinhong; Tan, Si Hui; Koh, Winston Lian Chye et al. (2013) Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342:1226-30