Hemopoietic stem cells (HSC), the earliest hematologic parent cells, can differentiate into all mature blood cell lineages. HSC maintain hemopoiesis throughout an animal's lifetime and can reconstitute hemopoiesis after transplantation into an irradiated recipient. The in vivo behavior of HSC cannot be observed directly, but rather must be inferred from observations of the behavior of derivative cell populations. The goal of this competitive renewal application is to use multiple independent, yet complementary biological and mathematical approaches, to define the kinetics of HSC in cats and mice. Specifically, we will analyze the contributions of feline HSC (labeled by viral gene transfer) to granulopoiesis, erythropoiesis, and lymphopoiesis after limiting dilution transplantations. These results will be compared to the outcomes predicted from computer simulations based on the analysis of data from G6PD heterozygous (female Safari) cats. As a second approach, we will estimate the rate of feline HSC replication by observing the pace (with age) of telomere shortening in granulocytes, lymphocytes, and marrow cells. In additional studies, the importance of apoptosis in maintaining HSC homeostasis will be investigated in cats and in mice, by analyzing the consequences of the overexpression in HSC of Bcl-2 (or Bcl-XL). The physiologic fate of circulating HSC will be explored in studies of parabiotic mice. Bayesian inference tools will be applied to statistical problem of estimating the frequencies of HSC and the average rates of HSC replication, apoptosis, and differentiation. By analyzing HSC kinetics in cats and mice, experimental systems with vastly different hemopoietic demands, we hope to gain insights that will allow an extrapolation to human hemopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046598-11
Application #
6628139
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Thomas, John
Project Start
1991-05-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
11
Fiscal Year
2003
Total Cost
$376,084
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Xu, Jason; Wang, Yiwen; Guttorp, Peter et al. (2018) Visualizing hematopoiesis as a stochastic process. Blood Adv 2:2637-2645
Catlin, Sandra N; Busque, Lambert; Gale, Rosemary E et al. (2011) The replication rate of human hematopoietic stem cells in vivo. Blood 117:4460-6
Roeder, Ingo; d'Inverno, Mark; other participants (2009) New experimental and theoretical investigations of hematopoietic stem cells and chronic myeloid leukemia. Blood Cells Mol Dis 43:88-97
Fong, Youyi; Guttorp, Peter; Abkowitz, Janis (2009) BAYESIAN INFERENCE AND MODEL CHOICE IN A HIDDEN STOCHASTIC TWO-COMPARTMENT MODEL OF HEMATOPOIETIC STEM CELL FATE DECISIONS. Ann Appl Stat 3:1696-1709
Shepherd, Bryan E; Kiem, Hans-Peter; Lansdorp, Peter M et al. (2007) Hematopoietic stem-cell behavior in nonhuman primates. Blood 110:1806-13
Abkowitz, Janis L; Chen, Jing (2007) Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones. Blood 109:5186-90
Chen, Jing; Larochelle, Andre; Fricker, Simon et al. (2006) Mobilization as a preparative regimen for hematopoietic stem cell transplantation. Blood 107:3764-71
Catlin, Sandra N; Guttorp, Peter; Abkowitz, Janis L (2005) The kinetics of clonal dominance in myeloproliferative disorders. Blood 106:2688-92
Lucas, M Lee; Seidel, Nancy E; Porada, Christopher D et al. (2005) Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes. Blood 106:51-8
Shepherd, Bryan E; Guttorp, Peter; Lansdorp, Peter M et al. (2004) Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths. Exp Hematol 32:1040-50

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