Pathogenesis and therapy of dense deposit disease in a mouse model

 说明(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，如果没有适当的调控，激活的补体可以引起炎症损伤。最近的研究发现，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，致密沉积病(DDD)是由于补体激活的替代途径(AP)调节失调而引起的一种罕见的肾脏疾病。DDD的特点是肾小球基底膜内存在电子致密沉积。DDD也称为膜增生性肾小球肾炎II型(MPGN II型)，属于新近提出的C3肾小球病变，其定义是以C3积聚为特征的肾小球病变，没有或仅有有限的免疫球蛋白沉积。大约10%的DDD患者还出现视力问题，视网膜色素上皮细胞下有致密沉积物，类似老年性黄斑变性患者眼睛中的玻璃体沉积。DDD的预后很差，因为目前的治疗大多是非特异性的，大约50%的患者最终进展为终末期肾功能衰竭。由于缺乏合适的动物模型，人类DDD的机制和治疗研究一直受到阻碍。我们最近建立了一个显示肾脏和视网膜病理的DDD的健壮小鼠模型。本研究的目的是利用这一新的小鼠模型，研究补体介导的DDD肾脏和视网膜损伤的发病机制，并检测各种抗补体药物在预防或逆转肾脏和眼部病变方面的活性。我们的长期目标是更好地了解调节失调的AP补体是如何导致DDD和其他补体介导的炎症性疾病的，并为开发针对此类人类疾病的新型抗补体疗法提供原则证据。

 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.