FVIII (FVIII) is the plasma protein deficient or functionally defective in hemophilia A, an X-chromosome linked bleeding disorder affecting 1/5,000 males. Affected patients experience significant morbidity and mortality related to repeated and/or life-threatening bleeding events. Protein replacement therapy with recombinant-derived FVIII is presently the preferred therapy. However, the cost of recombinant FVIII and the continued problem ofimmunogenicity remain significant problems. The long term goal of the proposed research is to provide fundamental insight into the regulation of FVIII synthesis and secretion with the ultimate goal of developing improved therapies for hemophilia A.
The specific aims of this proposal are to test the following three hypotheses: FVIII secretion is limited by transient aggregation immediately after its translation. We will characterize the requirements for ATP-dependent dissociation of FVIII aggregates. FVIII expression is toxic to cells by activation or ER stress-response signaling kinases. We will determine whether accumulation of FVIII within the ER activates protein kinases to inhibit protein synthesis and induce transcription of genes encoding ER stress proteins. ERGIC-53 is a molecular chaperone that interacts with the B domains or FV (FV) and F VIII and facilitates their transport to the Golgi compartment. We will elucidate the requirement of ERGIC-53 in the transport of FV and FVIII to the Golgi compartment. These studies will identify folding pathways of FVIII, improve FVIII secretion efficiency and limit toxicity associated with FVIII expression. In addition, these studies will identify how deficiency in ERGIC-53 causes combined deficiency of FV and FVIII. They will provide fundamental new insights into FVIII protein synthesis and secretion. The information will be vital to the future development of improved gene therapy protocols for hemophilia A. The ER provides an essential function to promote folding of proteins destined for the cell surface. Elucidating the mechanisms of protein folding, retention, and transport through the ER will have impact on the ability to therapeutically intervene in disease states that are associated with defective protein folding in the ER.
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