The molecular basis of intestinal stem cell biology in both humans and mice is a subject of active research. The goal of this application is to identify the mediators that influence the interaction of human intestinal stem cells with intestinal myofibroblasts in order to enhance the regeneration of human small bowel epithelium. This is a necessary step toward the development of novel cellular therapies for disorders associated with intestinal failure in children. To bring such therapies to the clinic, it will be essential to recapitulate the in situ characteristics of the intestinal epithelium. We will focus on assessing te mechanism by which human intestinal stem cells undergo self-renewal and differentiation. Specifically, we will assess the role of R-Spondin and WNT5a in maintaining stemness of these cells. We will also assess the mechanism by which Hedgehog signaling and the stress induced by alterations of oxygen tension and pH modulate the interaction between intestinal stem cells and myofibroblasts. Lastly, we will assess whether specific laminin and integrin isotypes alter intestinal stem cell growth and differentiation, and whether they affect cellular engraftment in recipient animal models. At the completion of this study, we anticipate that we will be able to define the mediators that control these stem cell characteristics, which will lead to novel cellula therapies.

Public Health Relevance

Our understanding of intestinal stem cell biology has increased dramatically over the last five years. The goal of this grant application is to use human intestinal samples to understand how intestinal stem cells are influenced by stress condition that alters how they divide and mature, and the role of other cells in the intestine that controls these changes. We believe that at the completion of this study, we will be able to define the mediators that control these stem cell characteristics, which will lead to novel cellular therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK085535-06
Application #
8774809
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (M3))
Program Officer
Carrington, Jill L
Project Start
2009-09-30
Project End
2019-08-31
Budget Start
2014-09-10
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$301,453
Indirect Cost
$105,704
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Jabaji, Ziyad; Brinkley, Garrett J; Khalil, Hassan A et al. (2014) Type I collagen as an extracellular matrix for the in vitro growth of human small intestinal epithelium. PLoS One 9:e107814
Hartman, Kira G; Bortner Jr, James D; Falk, Gary W et al. (2014) Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems. Exp Biol Med (Maywood) 239:1108-23
Lei, Nan Ye; Jabaji, Ziyad; Wang, Jiafang et al. (2014) Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 9:e84651
Magness, Scott T; Puthoff, Brent J; Crissey, Mary Ann et al. (2013) A multicenter study to standardize reporting and analyses of fluorescence-activated cell-sorted murine intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 305:G542-51
Stelzner, Matthias; Helmrath, Michael; Dunn, James C Y et al. (2012) A nomenclature for intestinal in vitro cultures. Am J Physiol Gastrointest Liver Physiol 302:G1359-63
Lahar, Nicholas; Lei, Nan Ye; Wang, Jiafang et al. (2011) Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium. PLoS One 6:e26898