Pathogenesis and therapy of dense deposit disease in a mouse model

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Complement is a part of innate immunity and plays a key role in host defense. However, if not properly regulated, activated complement can cause inflammatory injury. Recent works have identified complement as a major pathogenic pathway in many human immunological and inflammatory diseases. Among them, dense deposit disease (DDD) is a rare kidney disease caused by dysregulation of the alternative pathway (AP) of complement activation. DDD is characterized by the presence of electron- dense deposits within the glomerular basement membrane of the kidney. Known also as membranoproliferative glomerulonephritis type II (MPGN type II), DDD belongs to the recently introduced pathological entity called C3 glomerulopathy whose definition is glomerular pathology characterized by C3 accumulation with no or limited immunoglobulin deposition. Approximately 10% of DDD patients also develop vision problems with dense deposits underneath retinal pigment epithelial cells that resemble drusen deposits in the eyes of age-related macular degeneration patients. Prognosis of DDD is poor since current treatments are largely nonspecific and about 50% patients eventually progress to end stage renal failure. Mechanistic and therapeutic studies of human DDD have been hampered by the lack of appropriate animal models. We have recently generated a robust mouse model of DDD displaying both kidney and retinal pathologies. The objective of this application is to use this novel mouse model to investigate the pathogenic mechanisms of complement-mediated kidney and retinal injury in DDD and to test the activity of various anti-complement agents in preventing or reversing the kidney and eye pathologies. Our long term goal is to better understand how dysregulated AP complement leads to DDD and other complement-mediated inflammatory disorders and to provide proof of principle for developing novel anti-complement therapies for such human diseases.