Long-term objectives and specific aims: (1) To maintain and utilize in individual studies and in collaborative investigations a long-established inbred colony of bleeder animals (canine hemophilia A and B, canine von Willebrand disease, and polygenic canine hemophilia A/von Willebrand disease) as models of human disease to study mechanisms of disease, genetics, pathophysiology, replacement therapy, and gene therapy in these animal models; to apply and extend significant findings to the bleeder counterparts in man and animals. (2) To study the role of the factor VIII/von Willebrand factor complex in hemostasis, employing the several genotypes of the hemophilia A and von Willebrand disease strains of inbred bleeder animals; and to determine the effect of genotype on pharmacokinetics of infused recombinant plasma proteins. (3) To investigate the mechanism of action, molecular biology, and pathophysiologic hemostatic effects of the Bothrops factor, botrocetin and analogs, including studies in normal hemostasis and in induced disease (e.g., an animal model of thrombotic thrombocytopenia). (4) The main methodologies employed include chromatography of various types for protein purification, bioassays and immunoassay for procoagulants, ELISA, immunohistochemistry, immunogold electron microscopy, flow cytometry, gel eletrophoresis, radiolabeled polynucleotides, PCR analysis and screening procedures for cDNA libraries. Standard clotting tests and platelet characterization by aggreometry and macroscopic agglutination tests will be used.
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