The control of proliferation of hematopoietic stem and progenitor cells in vivo is most likely the end result of the production and action of growth-stimulating and growth-suppressing molecules. We have defined and characterized the influence of purified natural and recombinant molecules such as acidic isoferritins, the interferons gamma, alpha and beta, the E type prostaglandins, and tumor necrosis factor on normal and abnormal hematopoiesis. Of much interest to us, and potentially of great importance and relevance to an understanding of the physiological regulation of hematopoietic cell proliferation in vivo and of abnormalities in this regulation during leukemia and related blood disorders is the recent findings by us and others that certain molecules can synergise with each other in vitro so that the effects noted are much greater than additive. We propose to investigate the phenomenon of synergism between molecules in vitro and in vivo.
Our aims are to evaluate further and more precisely the actions and interactions alone and in combination of well-characterized and purified natural or recombinant acidic isoferritins, interferons-gamma and -alpha, prostaglandin E1 or E2 and tumor necrosis factor on the growth in vitro of fresh primary normal human and murine myeloid cells, on cells from patients with leukemia and related disorders, and on established human myeloid leukemia cell lines in vitro. Our goal is to study these molecule-cell interactions using pure molecules and purified populations of target cells, isolated by biophysical and immunological procedures, in the presence and absence of serum. Studies in vitro will include an analysis of the activity of these molecules using colony forming cell assays (CFU-GM, BFU-E, CFU-GEMM, S-cells), the receptor-binding capacity of these molecules, and effects of these molecules on the expression of proto-oncogenes. We also propose to evaluate the separate and combined actions of these molecules in vivo in mice undergoing rebound myelopoiesis, in untreated mice, and in mice infected with the Friend Viruis Complex. We believe that the studies proposed will increase our understanding of the relevance of these molecules and the concept of synergism as it applies to normal and abnormal regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036740-05
Application #
3174320
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-07-01
Project End
1991-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
5
Fiscal Year
1987
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
Shen, R N; Wu, B; Lu, L et al. (1994) Recombinant human interleukin-1 alpha: a potent bio-immunomodifier in vivo in immunosuppressed mice induced by cyclophosphamide, retroviral infection and surgical stress. In Vivo 8:59-63
Mantel, C R; Schulz, A R; Miyazawa, K et al. (1993) Kinetic selectivity of cholinephosphotransferase in mouse liver: the Km for CDP-choline depends on diacylglycerol structure. Biochem J 289 ( Pt 3):815-20
Broxmeyer, H E; Hangoc, G; Cooper, S et al. (1992) Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A 89:4109-13
Broxmeyer, H E; Hangoc, G; Cooper, S (1992) Clinical and biological aspects of human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells. Bone Marrow Transplant 9 Suppl 1:7-10
Vadhan-Raj, S; Broxmeyer, H E; Hittelman, W N et al. (1992) Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level. J Clin Oncol 10:1266-77
Broxmeyer, H E (1992) Suppressor cytokines and regulation of myelopoiesis. Biology and possible clinical uses. Am J Pediatr Hematol Oncol 14:22-30
Broxmeyer, H E; Cooper, S; Yoder, M et al. (1992) Human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells. Curr Top Microbiol Immunol 177:195-204
Broxmeyer, H E; Hangoc, G; Zucali, J R et al. (1991) Effects in vivo of purified recombinant human activin and erythropoietin in mice. Int J Hematol 54:447-54
Falkenburg, J H; Harrington, M A; de Paus, R A et al. (1991) Differential transcriptional and posttranscriptional regulation of gene expression of the colony-stimulating factors by interleukin-1 and fetal bovine serum in murine fibroblasts. Blood 78:658-65
Miyazawa, K; Hendrie, P C; Mantel, C et al. (1991) Comparative analysis of signaling pathways between mast cell growth factor (c-kit ligand) and granulocyte-macrophage colony-stimulating factor in a human factor-dependent myeloid cell line involves phosphorylation of Raf-1, GTPase-activating protein and m Exp Hematol 19:1110-23

Showing the most recent 10 out of 108 publications