The overall objective of the proposed study is to delineate the parameters that permit the long-term engraftment and expression of fetal and adult hematopoietic stem cells (HSC) transplanted in utero without cytoablation and without graft-vs-host disease (GVHD). Specifically, we will the sheep as the large animal experimental model to achieve more efficient HSC engraftment by a) determining the optimal concentrations of fetal and adult sheep cells that will result in the most efficient HSC engraftment, b) the effect of upmodulation of HSC homing receptor activity on donor cell engraftment, and c) the role of donor T cell subsets in grafting efficiency and GVHD. Modulation of homing receptor activity and in vitro transduction of autologous HSC will be used to study a) the mechanism(s) underlying the naturally occurring switches in primary sites of hematopoiesis from yolk sac to liver and bone marrow during ontogeny, and b) the role of bone marrow (and liver) in blood cell production during the early prenatal periods. It is hoped that the in utero HSc transplantation procedures developed here will permit the treatment of some lymphohematopoietic disorders in utero before the disease has had a chance to clinically compromise the patient.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049042-06
Application #
3569300
Study Section
Special Emphasis Panel (ZRG4-HEM-1 (02))
Project Start
1992-09-01
Project End
2002-08-31
Budget Start
1997-09-05
Budget End
1998-08-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sierra Biomedical Research Corporation
Department
Type
DUNS #
783285752
City
Reno
State
NV
Country
United States
Zip Code
89502
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Porada, Christopher D; Park, Paul J; Almeida-Porada, Graca et al. (2005) Gestational age of recipient determines pattern and level of transgene expression following in utero retroviral gene transfer. Mol Ther 11:284-93
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Almeida-Porada, Graca; Porada, Christopher; Zanjani, Esmail D (2004) Plasticity of human stem cells in the fetal sheep model of human stem cell transplantation. Int J Hematol 79:1-6

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