HUMAN TISSUE FACTOR AND ITS PLASMA INHIBITOR

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DESCRIPTION: (Investigator's abstract) Tissue factor pathway inhibitor (TFPI) is a critical regulator of tissue factor induced coagulation. The overall goals of this proposal are to further delineate the structures within the TFPI molecule that mediate its specific functional properties and to better define the physiologic role of TFPI through the use of mouse models. The specific aims are: 1) determine the structure of 34 kDa TFPI bound in plasma by low density lipoproteins (LDL) and determine the mechanisms underlying this association; 2) investigate the mechanisms of TFPI association with cell surfaces by examining the structure and properties of a mammalian expressed rTFPI which lacks this attribute; 3) further characterize TFPIK1 gene-disrupted mice which have an isolated deficiency in TFPI-mediated factor VIIa/TF inhibition; 4) produce TFPI null mice and compare their phenotype with that of TFPIK1 mice; and 5) attempt to rescue TFPIK1 (-/-) mice from intrauterine mortality with doxycycline-regulated transgene expression of TFPI to permit the evaluation of the physiologic role of TFPI in adult animals.