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.
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