Hematopoietic stem cells (HSCs) have the capacity to generate all the cells of the blood. A defining feature of HSCs is their ability to perpetuate themselves through self-renewal. While the phenotypic and functional properties of HSCs have been extensively characterized a fundamental question that remains unanswered is how self-renewal is regulated. Our work has revealed that I_-catenin,a key mediator of Wnt signaling, can promote self-renewal of HSC in vitro. Moreover, Axin, which enhances _-catenin degradation, causes inhibition of growth and reconstitution by HSC. These studies reveal an important role for 13-cateninin the regulation of HSC growth and self-renewal. To further elucidate the role of Wnt and {3-cateninsignaling in HSC, we propose to 1) Determine whether Wnt signaling regulates HSC function in vivo, 2) Examine whether the effects of I_-catenin and Axin on HSC reflect the activity of Wnt proteins and 3) Identify the molecular mechanisms by which I_-catenin exerts its effects on HSC self-renewal. These studies will not only advance our understanding of self-renewal, a key characteristic of all stem cells, but will also help develop strategies for in vitro expansion of stem cells, and thereby contribute to improving transplantation therapies for hematopoietic and degenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063031-08
Application #
7761256
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Wright, Daniel G
Project Start
2003-04-01
Project End
2010-12-31
Budget Start
2010-02-01
Budget End
2010-12-31
Support Year
8
Fiscal Year
2010
Total Cost
$196,394
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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