Molecular characterization of the factor VIII/Von Willebrand factor interaction.
dc.contributor.author | Cacheris, Phillip Michael | en_US |
dc.contributor.advisor | Ginsburg, David | en_US |
dc.date.accessioned | 2014-02-24T16:21:27Z | |
dc.date.available | 2014-02-24T16:21:27Z | |
dc.date.issued | 1995 | en_US |
dc.identifier.other | (UMI)AAI9527594 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9527594 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/104441 | |
dc.description.abstract | Von Willebrand factor (vWF) is a multimeric plasma glycoprotein which mediates the adhesion of the initial platelet plug to sites of vascular injury. vWF also serves as the carrier for factor VIII (FVIII) in the circulation and is necessary for FVIII stabilization. Qualitative or quantitative abnormalities of vWF result in the inherited bleeding disorder, von Willebrand disease (vWD). This thesis focuses on the interaction of FVIII and vWF. Initial studies identify a single nucleotide substitution, resulting in the substitution of Gln for Arg91, associated with the disproportionately decreased FVIII levels seen in a patient with a variant of vWD. Recombinant vWF carrying this mutation demonstrated markedly decreased FVIII binding function. This and similar mutations have now been identified in additional patients and appears to explain an unusual form of hemophilia associated with autosomal recessive inheritance. In order to further characterize the FVIII binding function of vWF, two different recombinant mutagenesis approaches were undertaken. A truncated vWF protein containing a 272 residue N-terminal fragment of mature vWF subunit corresponding to the proposed FVIII binding domain was expressed by transfection of heterologous cells. Failure of this isolated recombinant fragment to bind FVIII may suggest that other portions of vWF are required for proper folding and reconstitution of the FVIII binding function. In addition, recombinant full-length vWF mutants containing alanine substitutions at charged amino acids from Arg5 to Asp133 were assayed for FVIII binding. In this analysis, a number of noncontiguous segments involved in FVIII binding were potentially identified. Taken together, the studies described in this thesis begin to detail a more complete picture of the FVIII binding domain within vWF. | en_US |
dc.format.extent | 95 p. | en_US |
dc.subject | Biology, Molecular | en_US |
dc.subject | Biology, Genetics | en_US |
dc.title | Molecular characterization of the factor VIII/Von Willebrand factor interaction. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Cellular and Molecular Biology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/104441/1/9527594.pdf | |
dc.description.filedescription | Description of 9527594.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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