Abstract

Cyclic hematopoiesis is an inherited disease of man and grey collie dogs caused by a defect in bone marrow regulation of blood cell production. Since bone marrow transplants can transfer this disease in both dogs and man, it is considered a disease of hematopoietic stem cells. Lithium and endotoxin treatment eliminate neutrophil cycling in the dogs while prednisone eliminates cycling in some patients. Recent cell culture studies have shown that there is a cyclic variation in the flow of cells from the primitive stem cell population into more differentiated precursor cell populations and preliminary biochemical studies have shown marked alterations in purine and pyrimidine nucleotides in erythrocytes of both dogs and patients. In the proposed work, we will perform in vitro bone marrow culture studies using both short term and long term culture techniques and biochemical studies of purine and pyrimidine nucleotides, nucleosides and bases using high pressure liquid chromatography. This two-pronged approach is intended to delineate the precise defect in hematopoietic regulation which causes this disease. Dogs and patients with cyclic hematopoiesis also will be treated with various therapies, including lithium and glucocorticosteriods, and the effects of these therapies on the cellular and biochemical abnormalities associated with the disease will be measured. We expect this combined approach will reveal new insights into the normal hematopoietic regulatory systems and may suggest novel therapeutic approaches to this and related hematologic diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK018951-10S1
Application #
3226233
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1980-07-01
Project End
1987-03-31
Budget Start
1985-07-01
Budget End
1987-03-31
Support Year
10
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Aprikyan, Andrew A G; Kutyavin, Tatyana; Stein, Steven et al. (2003) Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp Hematol 31:372-81
Aprikyan, Andrew A G; Liles, W Conrad; Boxer, Laurence A et al. (2002) Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia. J Pediatr Hematol Oncol 24:784-6
Dale, D C; Liles, W C; Garwicz, D et al. (2001) Clinical implications of mutations of neutrophil elastase in congenital and cyclic neutropenia. J Pediatr Hematol Oncol 23:208-10
Aprikyan, A A; Dale, D C (2001) Mutations in the neutrophil elastase gene in cyclic and congenital neutropenia. Curr Opin Immunol 13:535-8
Aprikyan, A A; Liles, W C; Rodger, E et al. (2001) Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood 97:147-53
Dale, D C; Person, R E; Bolyard, A A et al. (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96:2317-22
Aprikyan, A A; Liles, W C; Park, J R et al. (2000) Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 95:320-7
Horwitz, M; Benson, K F; Person, R E et al. (1999) Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 23:433-6
Dale, D C (1998) The discovery, development and clinical applications of granulocyte colony-stimulating factor. Trans Am Clin Climatol Assoc 109:27-36;discussion 36-8
Palmer, S E; Stephens, K; Dale, D C (1996) Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 66:413-22

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