Abstract

The overall goals of the proposed work are: (i) to further establish the use of retrovirus-mediated gene transfer as a means for introducing genes into hematopietic cells, and as an approach for studying the properties of hematopietic stem cells, and (ii) to generate new information bearing on the feasibility of gene transfer as a therapy for human diseases affecting the hematopoietic system. The proposed experiments in the mouse focus predominantly on the use of gene transfer to study the processes of hematopoietic stem cell proliferation and differentiation, and to define the parameters that govern the expression of genes introduced into mature hematopoietic cell types via stem cell infection. These studies will involve the extensive characterization of hematopoietic tissue derived from long term bone marrow transplant recipients previously engrafted with retrovirus transduced stem cells. Assessment of the developmental potential of general properties of hematopoietic stem cells will rely on the use of recombinant proviruses introduced into stem cell DNA as unique clonal markers. Studies are also proposed to examine the transduction of human hematopoietic stem cells, and to establish a framework for studying the expression of genes introduced into those cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037569-03
Application #
3353347
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142

  Publications

Goodell, M A; Brose, K; Paradis, G et al. (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183:1797-806
Sadelain, M; Wang, C H; Antoniou, M et al. (1995) Generation of a high-titer retroviral vector capable of expressing high levels of the human beta-globin gene. Proc Natl Acad Sci U S A 92:6728-32
Riviere, I; Brose, K; Mulligan, R C (1995) Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells. Proc Natl Acad Sci U S A 92:6733-7
Karaplis, A C; Luz, A; Glowacki, J et al. (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8:277-89
Dranoff, G; Crawford, A D; Sadelain, M et al. (1994) Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264:713-6
Silver, D P; Spanopoulou, E; Mulligan, R C et al. (1993) Dispensable sequence motifs in the RAG-1 and RAG-2 genes for plasmid V(D)J recombination. Proc Natl Acad Sci U S A 90:6100-4
Spain, L M; Mulligan, R C (1992) Purification and characterization of retrovirally transduced hematopoietic stem cells. Proc Natl Acad Sci U S A 89:3790-4
Tybulewicz, V L; Crawford, C E; Jackson, P K et al. (1991) Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65:1153-63
Collins, M K; Malde, P; Miyajima, A et al. (1990) Evidence that the level of the p55 component of the interleukin (IL) 2 receptor can control IL 2 responsiveness in a murine IL 3-dependent cell. Eur J Immunol 20:573-8
Stuhlmann, H; Jaenisch, R; Mulligan, R C (1989) Construction and properties of replication-competent murine retroviral vectors encoding methotrexate resistance. Mol Cell Biol 9:100-8

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