The proposed project is directed towards elucidating those factors that regulate early events in human megakaryocytic differentiation. The following studies will be performed: (1) Examination of the effect of platelet microparticles present in human serum and plasma on in vitro megakaryocytopoiesis. (2) Examination of the effect of aplastic anemia serum on the release of megakaryocyte colony stimulating activity by peripheral blood cells. (3) Identification of megakaryocyte colony stimulating activity in media conditioned by various human tissues and human continuous cell lines. (4) Isolation and characterization of megakaryocyte colony stimulating activity. (5) Production of polyclonal and monoclonal antibodies to megakaryocyte colony stimulating activity. (6) Development of a radioimmunoassay for megakaryocyte colony stimulatilng activity. (7) Determination of the specificity of action of megakaryocyte colony stimulating activity. (8) Use of polyclonal and monoclonal antibodies to localize the site of production of megakaryocyte colony stimulating activity immunocytochemical techniques. The completion of this project will result in important information concerning both hematopoietic stem cell differentiation in general and in specific megakaryocytic differentiation. These studies will determine if the stimulating activity observed in aplastic anemia serum is the result of the presence of a regulatory molecule or merely the result of the absence of an inhibitor. Purification of megakaryocyte colony stimulating activity will allow more careful studies of its biological effects and hopefully will allow one to evaluate the use of this hematopoietic regulatory macromolecule as a therapeutic tool in thrombocytopenic cancer patients. The development of a radioimmunoassay for megakaryocyte colony stimulating activity will allow us to study perturbations of this regulatory substance in disease states. Localization of the site of production will hopefully result in the isolation of its cell of origin and investigation of the regulation of the production of this factor at the cellular level. This information will be of use to both biologists and clinicans who are interested in cancer biology and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034841-09
Application #
3172671
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1982-09-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Briddell, R A; Brandt, J E; Leemhuis, T B et al. (1992) Role of cytokines in sustaining long-term human megakaryocytopoiesis in vitro. Blood 79:332-7
Briddell, R A; Bruno, E; Cooper, R J et al. (1991) Effect of c-kit ligand on in vitro human megakaryocytopoiesis. Blood 78:2854-9
Bruno, E; Cooper, R J; Briddell, R A et al. (1991) Further examination of the effects of recombinant cytokines on the proliferation of human megakaryocyte progenitor cells. Blood 77:2339-46
Briddell, R A; Hoffman, R (1990) Cytokine regulation of the human burst-forming unit-megakaryocyte. Blood 76:516-22
Hoffman, R; Briddell, R; Bruno, E (1990) Numerous growth factors can influence in vitro megakaryocytopoiesis. Yale J Biol Med 63:411-8
Straneva, J E; Briddell, R A; McDonald, T P et al. (1989) Effects of thrombocytopoiesis-stimulating factor on terminal cytoplasmic maturation of human megakaryocytes. Exp Hematol 17:1122-7
Briddell, R A; Brandt, J E; Straneva, J E et al. (1989) Characterization of the human burst-forming unit-megakaryocyte. Blood 74:145-51
Straneva, J E; Briddell, R A; Hui, S L et al. (1989) Serum from patients with various thrombopoietic disorders alters terminal cytoplasmic maturation of human megakaryocytes in vitro. Eur J Haematol 42:293-7
Srivastava, A; Boswell, H S; Heerema, N A et al. (1988) KRAS2 oncogene overexpression in myelodysplastic syndrome with translocation 5;12. Cancer Genet Cytogenet 35:61-71
Roth, B J; Sledge Jr, G W; Straneva, J E et al. (1988) Analysis of phorbol ester stimulated human megakaryocyte development. Blood 72:202-7

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