Pathogenesis and therapy of dense deposit disease in a mouse model

 描述（由申请人提供）：补体是先天免疫的一部分，在宿主防御中起关键作用。然而，如果不适当调节，活化的补体可引起炎性损伤。最近的工作已经确定补体是许多人类免疫性和炎症性疾病的主要致病途径。其中，致密存款病（DDD）是一种罕见的肾脏疾病，由补体激活的旁路途径（AP）失调引起。DDD的特征是在肾脏的肾小球基底膜内存在电子致密沉积物。DDD也称为II型膜增生性肾小球肾炎（MPGN II型），属于最近引入的称为C3肾小球病的病理实体，其定义为肾小球病理学，特征为C3蓄积，无或有限的免疫球蛋白沉积。大约10%的DDD患者还发展出视力问题，在视网膜色素上皮细胞下有致密沉积物，类似于年龄相关性黄斑变性患者眼中的玻璃疣沉积物。DDD的预后很差，因为目前的治疗在很大程度上是非特异性的，大约50%的患者最终进展为终末期肾衰竭。由于缺乏合适的动物模型，人类DDD的机制和治疗研究受到阻碍。我们最近产生了一个强大的DDD小鼠模型，显示肾脏和视网膜病变。本申请的目的是使用这种新的小鼠模型来研究DDD中补体介导的肾脏和视网膜损伤的致病机制，并测试各种抗补体剂在预防或逆转肾脏和眼睛病理中的活性。我们的长期目标是更好地了解AP补体失调如何导致DDD和其他补体介导的炎症性疾病，并为开发针对此类人类疾病的新型抗补体疗法提供原理证明。

 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.