The candidate has been interested in pursuing a career in academic medicine since graduating from medical school in 1976. After completing 4 years of clinical training in internal medicine and nephrology he entered the laboratory of Dr. William G. Couser for training in renal immunology and subsequently joined the faculty at the University of Washington when Dr. Couser moved there in 1982. Since then the applicant has continued to work with Dr. Couser as well as expanding his own interests in the field of immunologic renal disease, including work on the role of the complement system in renal injury. The complement (C) system is a well established mediator of immune renal injury, both through its recruitment of inflammatory cells and by a direct, cell-independent effect, originally demonstrated in this laboratory. Work in C6 deficient rabbits has suggested that the terminal complement components are involved in C-mediated injury in membranous nephropathy and anti-GBM nephritis. This proposal will further explore the participation of the terminal C cascade in the production of C-mediated immune renal injury. Using animal models of glomerular disease due to immune deposits in the mesangium, GBM and subepithelial space we will correlate the presence or absence of the distal complement components and the neoantigens of the membrane attack complex (MAC) with the role of the C system in producing injury. To specifically substantiate the importance of the distal pathway, we will look at the effects of genetic and antibody induced C component deficiencies on various models of glomerulonephritis and will perfuse kidneys having deposits formed in vivo with normal and C-deficient sera to assess their ability to mediate injury. The role of the distal pathway in contributing to chronicity of disease will be assessed in non-immunological models of sclerosis induced in C-deficient animals. We will also evaluate the ability of the C system to solubilize immune deposits formed in vivo and assess the importance of the individual C-components in this process. The equipment and facilities necessary to complete this project are already present in the Division of Nephrology. In addition to other faculty in the division, there are several highly trained investigators in other departments involved in the study of immune mediated renal injury, as well as research and training programs in immunologic renal disease and rheumatology.