The long-term objective of this research program is to gain new information about the structure and function of the various proteins that participate in blood coagulation as well as their biosynthesis and regulation. In the work proposed in the present grant, considerable emphasis will be placed on the study of human fibrinogen, including: 1) the mechanism by which it is assembled from the alpha, beta and gamma chains; 2) an examination of important regions in the molecule involved in polymerization, calcium binding, leukocyte adhesion, factor XIII binding, and the role of the extended alpha chain, and; 3) a study of the 5' regulatory region of the genes coding for the alpha and gamma chains. A second goal will be to focus on the mechanism of regulation for the gene coding for factor X. Three regulatory segments in the promoter region of the factor X gene have been identified and attempts will be made to isolate and clone these regulatory proteins. Another goal of this project is to establish the location of the disulfide bonds in the heavy and light chains of recombinant factor VIII and to determine the binding sites within factor VIII for factor IXa and factor X. An additional project proposed in this application will be to clarify the role of a metalloprotease isolated in our lab as well as furin in the processing of the proportion of the vitamin K-dependent proteins. Attempts will also be made to isolate other proteases that may be important in this processing step. Another goal of this project will be to carry out crystallographic studies of mutant forms of the """"""""a"""""""" subunit of human factor XIII. Particular emphasis will be placed on structural determination of mutations in the apparent catalytic site of the enzyme. Lastly, experiments are proposed to study the genes coding for the prostate specific antigen and human glandular kallikrein and how they are regulated in the prostate.
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