A Collaborative Study of Membranoproliferative Glomerulonephritis Type II

描述（由申请人提供）：膜增生性肾小球肾炎II型或致密沉积病（MPGNII/DDD）的特征是电子致密物质沉积在肾脏肾小球基底膜（GBM）和眼睛的布鲁氏膜内。诊断通常在5-15岁的儿童中进行。在10年内，这些儿童中约有一半进展为终末期肾病，偶尔伴有视力障碍的晚期合并症。在大多数MPGNII/DDD患者中，由于持续的C3降解而导致的补体不足可以通过低APH 50值、低Cs水平和Cs降解产物Csd的出现在血浆中得到证实。在几乎所有的同种异体移植中，肾移植都与疾病复发有关，并且移植最终失败的比例很高。MPGNII/DDD是一种复杂的疾病。我们假设：i)其病理生理与替代途径（AP） C3转换酶的失调有关，这导致补体AP的不受控制的激活；2)补体AP不受控制的激活发生在一个允许的遗传背景下；3)对GBM和Bruch膜的损伤是因为这两种膜对ap介导的补体损伤只有边缘保护。我们提供了支持这一假设的初步证据，表明因子H、因子H相关5和因子c的特定突变和/或等位基因与MPGNII/DDD相关。对于两个因子h相关的等位基因，AK224和H402，我们已经完成了功能研究，证明突变蛋白与野生型蛋白相比存在差异。在本次资助中，我们将完成三个具体目标，更详细地研究补体AP在MPGNII/DDD中的作用。具体目标是：1。具体目的1：检验几种补体相关基因的等位基因/突变与MPGNII/ ddd2相关的假设。特异性目标2：检验特异性目标中发现的相关等位基因/突变的假设！在功能水平上影响补体的AP特异性目的3：验证外源性小鼠因子H （mFH）可以挽救因子H缺陷小鼠（C/ft-/-） MPGNII/DDD表型的假设。

DESCRIPTION (provided by applicant): Membranoproliferative glomerulonephritis type II or Dense Deposit Disease (MPGNII/DDD) is characterized by the deposition of electron-dense material within the glomerular basement membrane (GBM) of the kidney and within Bruch's membrane in the eye. The diagnosis is usually made in children between the ages of 5-15 years. Within 10 years about half of these children progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. In most persons with MPGNII/DDD, hypocomplementemia due to continuous C3 degradation can be documented in plasma by low APH 50 values, low Cs levels, and the appearance of the Cs degradation product Csd. Renal transplantation is associated with disease recurrence in virtually all allografts and a high percentage of transplants ultimately fail. MPGNII/DDD is a complex disease. We hypothesize that: i) its pathophysiology is related to dysregulation of the alternative pathway (AP) C3 convertase, which leads to uncontrolled activation of the AP of complement; 2) uncontrolled activation of the AP of complement occurs on a permissive genetic background; and 3) damage to the GBM and Bruch's membrane occurs because these two membranes have only marginal protection from AP-mediated complement injury. We provide preliminary evidence to support this hypothesis by showing that specific mutations and/or alleles of Factor H, Factor H-Related 5 and Cs are associated with MPGNII/DDD. For two of the Factor H-associated alleles, the AK224 and H402, we have completed functional studies that demonstrate differences in the mutant proteins as compared to wild type protein. In this grant we will complete three specific aims to investigate in greater detail the role of the AP of complement in MPGNII/DDD. The specific aims are: 1. Specific Aim i: To examine the hypothesis that alleles/mutations in several complement-related genes are associated with MPGNII/DDD 2. Specific Aim 2: To examine the hypothesis that the associated alleles/mutations identified in Specific Aim ! affect the AP of complement at a functional level 3. Specific Aim 3: To examine the hypothesis that exogenous murine Factor H (mFH) can rescue the MPGNII/DDD phenotype in the Factor H deficient mouse (C/ft-/-)