The aim of this program is to further our understanding of the biology of hematopoietic stem cells and apply this knowledge to develop effective strategies for gene therapy. In studies evaluating novel mechanisms that may provide insights into the regulation of the proliferation and differentiation of stem cells, we will investigate: the role of stem cell interactions mediated by the Drosophila developmental gene, Notch, in determining the fate of stem cells (Project I); methods for inhibiting the retinoic acid pathway to achieve stem cell self renewal (Project II); the role of the bcl-2 gene family in maintaining stem cell survival and differentiation of immature hematopoietic cells (Project III); and the role of Max-interacting proteins in regulating stem cell proliferation and differentiation (Project IV). Results of these efforts will be applied in preclinical and clinical studies of the retroviral mediated transduction of hematopoietic stem cells. In studies to improve our ability to transduce stem cells, we will investigate the determinants of retrovirus entry into stem cells (Project V); and, in nonhuman primates, we will systematically evaluate treatments that elicit stem cells optimally susceptible to viral-mediated gene transduction (Project VI). As a model to evaluate current approaches and to incorporate new developments from this and other research programs, we will initiate a clinical trial of gene therapy for treating patients with leukocyte adhesion deficiency disease by introducing a normal CD18 gene into their hematopoietic stem cells (Project VII). Central to the success of these trials are Core programs which will provide human hematopoietic cells, isolate human and murine hematopoietic stem cells, and prepare retrovirus in large quantities for preclinical and clinical studies. By bringing together investigators with a range of expertise related to hematopoiesis and those with expertise in more basic cellular mechanisms, the SCOR program provides the necessary mechanism for generating novel approaches in this research arena.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL054881-05
Application #
6056317
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Varnum-Finney, Barbara; Dallas, Mari H; Kato, Keizo et al. (2008) Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus. Blood 111:2615-20
Piasecki, Julia C; Beagles, Karen; Beard, Brian C et al. (2008) Induction of transgene-specific cytotoxic T lymphocyte responses after transplantation of gene-modified CD34+ cells despite nonablative immunosuppressive conditioning. Hum Gene Ther 19:103-7
Gerull, Sabine; Beard, Brian C; Peterson, Laura J et al. (2007) In vivo selection and chemoprotection after drug resistance gene therapy in a nonmyeloablative allogeneic transplantation setting in dogs. Hum Gene Ther 18:451-6
Jung, Chul Won; Beard, Brian C; Morris, Julia C et al. (2007) Hematopoietic stem cell engraftment: a direct comparison between intramarrow and intravenous injection in nonhuman primates. Exp Hematol 35:1132-9
Si, Jutong; Mueller, LeMoyne; Collins, Steven J (2007) CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J Clin Invest 117:1412-21
Neff, Tobias; Gerull, Sabine; Peterson, Laura J et al. (2007) Improved short-term engraftment of lentivirally versus gammaretrovirally transduced allogeneic canine repopulating cells. J Gene Med 9:357-61
Si, Jutong; Mueller, LeMoyne; Schuler, Aaron et al. (2007) The retinoic acid receptor/CaMKII interaction: pharmacologic inhibition of CaMKII enhances the differentiation of myeloid leukemia cells. Blood Cells Mol Dis 39:307-15
Aoyama, Keisuke; Delaney, Colleen; Varnum-Finney, Barbara et al. (2007) The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation. Stem Cells 25:2488-97
Dallas, Mari H; Varnum-Finney, Barbara; Martin, Paul J et al. (2007) Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1. Blood 109:3579-87
Shepherd, Bryan E; Kiem, Hans-Peter; Lansdorp, Peter M et al. (2007) Hematopoietic stem-cell behavior in nonhuman primates. Blood 110:1806-13

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