Grant: Operating Grant

Hemophilia A is the most common severe inherited bleeding disorder. The disease is caused by inherited mutations of the clotting factor VIII (FVIII) gene that result in absent or low levels of FVIII or a FVIII protein that lacks function. Current treatment for hemophilia A involves frequent transfusions with FVIII protein. This treatment is safe and effective, but 25% of treated patients develop an immune response to the protein. The overall aim of this research program is to investigate details relating to how and where FVIII is produced and cleared from the blood. For each of these objectives, the impact on FVIII immunogenicity will be determined. The project's first aim will be to determine where and under what conditions FVIII is made by various cell types in the body. These studies will focus on the production of FVIII by the liver, by the lining cells of blood vessels, the endothelium, and by cells within the thymus where the immunologic education of lymphocytes takes place. These studies will involve the study of FVIII in cultured cells maintained under different environmental conditions and will also involve the study of mice in which the production of FVIII has been genetically disrupted in specific cell types. These experiments will tell us about cell type-specific and environmental influences on FVIII production and the impact of the site of FVIII production on immunogenicity. The second series of studies will focus on mechanisms involved in the removal of FVIII from blood. These studies will determine the role of two recently identified scavenger receptors that have been linked through genetic association studies to the regulation of FVIII levels. These studies will determine the cell types that possess these receptors, will assess the ability of FVIII to bind to the receptors with and without its partner protein, von Willebrand factor, and will investigate FVIII clearance and immunogenicity in mice in which these receptors have been deleted.