Abstract

The long-term objective of this application is to establish the role of human IL-3 in normal and malignant hemopoiesis. Specifically it is proposed to: 1.Establish the critical regions for activity of the IL-3 molecule by carrying out site-directed mutagenesis of the IL-3 gene; chemically synthesizing the IL-3 molecule; developing monoclonal antibodies to IL-3 that inhibit function. A multiple biological and receptor assay system will be used seeking to identify IL-3 mutants with selective function. 2.Study the regulation of production of the IL-3 molecule by examining: the IL-3 mRNA stability and translation; the transcription of the IL-3 gene seeking to identify regulatory sequences and new transcription factors. These studies may lead to new forms of therapies in patients with leukemia by developing specific tools to inhibit the response of leukemic cells to IL-3 or by inhibiting their IL-3 production.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045822-05
Application #
3189111
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-08-01
Project End
1993-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Institute of Medical and Vet Science
Department
Type
DUNS #
740198254
City
Adelaide
State
Country
Australia
Zip Code
5000

  Publications

Korpelainen, E I; Gamble, J R; Smith, W B et al. (1995) Interferon-gamma upregulates interleukin-3 (IL-3) receptor expression in human endothelial cells and synergizes with IL-3 in stimulating major histocompatibility complex class II expression and cytokine production. Blood 86:176-82
Vadas, M; Lopez, A; Gamble, J et al. (1994) Cytokines and allergy. J Allergy Clin Immunol 94:1289-93
Ryan, G R; Vadas, M A; Shannon, M F (1994) T-cell functional regions of the human IL-3 proximal promoter. Mol Reprod Dev 39:200-7
Hercus, T R; Bagley, C J; Cambareri, B et al. (1994) Specific human granulocyte-macrophage colony-stimulating factor antagonists. Proc Natl Acad Sci U S A 91:5838-42
Barry, S C; Bagley, C J; Phillips, J et al. (1994) Two contiguous residues in human interleukin-3, Asp21 and Glu22, selectively interact with the alpha- and beta-chains of its receptor and participate in function. J Biol Chem 269:8488-92
Hercus, T R; Cambareri, B; Dottore, M et al. (1994) Identification of residues in the first and fourth helices of human granulocyte-macrophage colony-stimulating factor involved in biologic activity and in binding to the alpha- and beta-chains of its receptor. Blood 83:3500-8
D'Andrea, R; Rayner, J; Moretti, P et al. (1994) A mutation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 that leads to ligand independence and tumorigenicity. Blood 83:2802-8
Kremer, E; Baker, E; D'Andrea, R J et al. (1993) A cytokine receptor gene cluster in the X-Y pseudoautosomal region? Blood 82:22-8
Goodall, G J; Bagley, C J; Vadas, M A et al. (1993) A model for the interaction of the GM-CSF, IL-3 and IL-5 receptors with their ligands. Growth Factors 8:87-97
Lopez, A F; Shannon, M F; Barry, S et al. (1992) A human interleukin 3 analog with increased biological and binding activities. Proc Natl Acad Sci U S A 89:11842-6

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