The development and differentiation of hematopoietic stem cells into mature progeny is critically dependent on their interactions with the stromal elements of the bone marrow. Stromal cells produce and sequester into their extracellular matrix cytokines that are essential for stem cell division and differentiation.
The aim of this proposal is to determine whether localized proteolysis, mediated by plasminogen activators and/or plasmin (the product of plasminogen activation by plasminogen activators), is an integral part of the chain of events leading to the release of effector molecules required for stem cell division and differentiation. Plasminogen activator activity is modulated by specific inhibitors, specific enzyme receptors and matrix macromolecules which may either inhibit or potentiate activity. In this manner, controlled pericellular proteolysis in the bone marrow stromal microenvironment, functions to modulate haemopoiesis via the proteolytic release of effector molecules. The regulation of plasminogen activator and plasminogen activator inhibitor activity in normal myeloid cells, in myeloid leukemic cell lines and in bone marrow stromal cells by factors such as the colony stimulating factors, basic fibroblast growth factor and transforming growth factor beta will be investigated. The interaction of the plasminogen activators with stromal cells and matrices will be examined. This will include the identification of specific binding molecules for tissue plasminogen activator on the surfaces of cells and in the matrix. The ability of inhibitors of plasminogen activator to perturb either normal myeloid differentiation and cell division, or matrix-induced differentiation of leukemic cell lines will be examined. The data generated during this project will yield new insights into the regulation of both normal leukemic myelopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049419-02
Application #
3193482
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
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Brunner, G; Metz, C N; Nguyen, H et al. (1994) An endogenous glycosylphosphatidylinositol-specific phospholipase D releases basic fibroblast growth factor-heparan sulfate proteoglycan complexes from human bone marrow cultures. Blood 83:2115-25
Metz, C N; Brunner, G; Choi-Muira, N H et al. (1994) Release of GPI-anchored membrane proteins by a cell-associated GPI-specific phospholipase D. EMBO J 13:1741-51
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Brunner, G; Nguyen, H; Gabrilove, J et al. (1993) Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood 81:631-8
Hannocks, M J; Oliver, L; Gabrilove, J L et al. (1992) Regulation of proteolytic activity in human bone marrow stromal cells by basic fibroblast growth factor, interleukin-1, and transforming growth factor beta. Blood 79:1178-84

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