This proposal, a blend of basic and clinically oriented research, is based on accomplishments achieved with the aid of our MERIT Award. Specifically, the following projects are proposed. I. We plan to extend our studies (Proc. Natl. Acad. Sci., USA 95, 537, 1998) on the interactions of double-headed peptide ligands with fibrin(ogen). (i) The peptide head groups will be connected with polyethyleneglycol tethers, longer and shorter than in the previous work (n=18), so as to determine optimal length for fibrin(ogen) assembly; (ii) head group peptides will be modified (up to ca. 20 residues) to reflect the N-terminal sequence of the alpha chain in fibrin; (iii) effectiveness of the synthetic compounds for promoting fibrinogen assembly in solution will be examined by a variety of physical techniques, and (iv) their influence on clotting times will be evaluated. II. Novel screens for the rapid diagnosis of disorders of fibrin stabilization and improved measurements of Factor XIIIa activity will be developed. III. Major focus will be an in-depth analysis of autoimmune inhibitors of fibrin stabilization, based on specimens we collected over the years from hemorrhagic patients. One of the inhibitors is directed against the crosslinking sites of the alpha chains of fibrin, the others against various determinants in Factor XIII. Precise identification of epitope recognitions by these autoimmune antibodies will be carried out in order to gain better insight into the basic structure-function relationships in fibrin stabilization and also for devising affinity procedures for removing the antibodies from the patient's circulation.
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