Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood is a biological phenomenon that is not understood at the molecular level and little is known about the physiologic importance of it. It is notable that there is significant inter-individual variability in humans and inter-strain variability in mice in the ability to mobilize hematopoietic stem and progenitor cells (HSPCs) suggesting that there is genetic regulation of mobilization. In the murine system, a locus on chromosome 11 has been linked to an inter-strain variation in granulocyte colony- stimulating factor (G-CSF) induced stem cell mobilization proficiency. The gene or genes regulating this variation may play an important role in localization and in trafficking of HSPCs. As there is a growing clinical need for hematopoietic stem cell based therapies, it will be important to understand the physiological regulation of stem cell localization, mobilization, and trafficking. This proposal aims at the identification of the gene on chromosome 11 that is a physiologic regulator of HSPC mobilization by generating sub-congenic animals and subsequent functional analysis of individual genes in the genomic interval linked to mobilization by RNA interference. We will also analyze the function of the locus/gene in trans-endothelial migration and adhesion of HSPCs. Finally, using congenic animals in competitive transplantation/mobilization assays, we will analyze the correlation between mobilization proficiency and trafficking of HSPCs to either non-hematopoietic niches, e.g. to muscle tissue, or to other hematopoietic niches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076604-04
Application #
7216803
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$282,558
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Geiger, Hartmut; Zheng, Yi (2013) Cdc42 and aging of hematopoietic stem cells. Curr Opin Hematol 20:295-300

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