The theme of this SCOR renewal application is to investigate the function of specific proteins carrying blood group antigens and their impact on health and disease. The objectives are: a) Link specific blood group genotypes with disease processes and develop understanding of the molecular basis for the disease; b) Determine structure/function relationships of clinically significant blood groups; and c) introduce to the blood banking community more precise and convenient methods for typing RBC antigens and for identifying antibodies. To accomplish more precise and convenient methods for typing RBC antigens and for identifying antibodies. To accomplish these goals we have a collaborative group composed of four projects and three core units: Project 1 aims to elucidate the functions of the Rh family of proteins, and requirements for expression of Rh antigens on the RBC surface. This is important in understanding clinical aspects of blood transfusion, autoimmune hemolytic anemia, and hemolytic disease of the newborn. Project 2 plans to define the functions of the Kell/XK complex. Kell participates in the activation of endothelins, which are involved in the regulation of vascular tone and lack of XK is associated with the McLeod syndrome. This project will also determine the mechanisms by which antibodies to associated with the McLeod syndrome. This project will also determine the mechanisms by which antibodies to Kell antigens suppress erythropoiesis and induce fetal anemia. Project 3 will identify the RBC receptors and the parasite ligands that are essential for plasmodium vivax and P. falciparum invasion and their specific interactions. This could lead to development of new prophylactic agents such as drugs or vaccines to prevent malaria. Project 4 will express protein carrying blood group antigens at levels equivalent to that on RBCs so as to develop an automated and objective method to detect and identify clinically- significant blood group antibodies. This project will also study diversity of blood group genes in different populations and to engineer clinically relevant monoclonal antibodies. Administrative, Cell Sorting, and Antibody Production core units support the projects. Overall the program provides an integrated approach for studying the molecular and cell biology of blood groups and applying the knowledge gained to modernize blood banking procedures and for developing detailed understanding of the functions of blood group antigens and their possible relations to human disease.