Cyclic hematopoiesis (CH) in man and the dog is a genetic disease characterized by periodic fluctuations in blood cells, particularly neutrophils. Many studies indicate that the fluctuations in circulating blood cells result from cyclic proliferation of the hematologic stem cell. A defect of unknown origin in extracellular to intracellular membrane signal transduction has recently been identified in platelets from CH dogs and human patients with CH disease, based on defective platelet aggregation to collagen and platelet activating factor, (PAF) and normal thromboxane production. The broad aims of these studies are to identify the specific cellular defects in human and canine CH platelets, determine if similar defects are present in neutrophils and lymphocytes and relate the defect(s) to cyclic cell proliferation. The majority of the specific aims are designed to determine if defects exist in the second messenger system of all blood cells of CH dogs and humans. Mathematical modeling of erythropoiesis and granulopoiesis in CH dogs will be used to further examine why granulopoiesis has stable cycles and erythropoiesis is mildly affected. The long term objective is to understand exactly how the cycles of hematopoiesis are brought about through alterations in controls of cell division and interactions among populations of cells. The following methodology will be used to achieve the specific aims: 1) Characterize the platelet second messenger defect by measuring cAMP concentrations and adenylate cyclase activity, cyclic nucleotide phosphodiesterase activity, calmodulin, calcium mobilization, inositol phospholipid metabolism, protein phosphorylations and platelet granule contents in CH and normal platelets. 2) Comparisons of CH and normal neutrophils response to secretogogues such as FMLP, PAF and A23187 in terms of threshold sensitivity, aggregation, receptor-mediated arachidonic acid release, degranulation and superoxide formation. 3) Compare normal and CH lymphocyte responses to mitogenic stimulation. 4) Compare proliferation activity of CH and normal bone marrow cultures (Dextersystem) to known growth modulators, and 5) Computer model erythropoiesis and granulopoiesis of normal and CH dogs. Identification of the biochemical defect(s) responsible for CH disease should provide a better understanding of the comparable blood disorder of humans. These studies cross multiple disciplines of biology and medicine and should contribute important new information on cell regulatory mechanisms in hematopoietic proliferative diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL015647-13
Application #
3334998
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1976-12-01
Project End
1988-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
13
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Type
Schools of Veterinary Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
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