A Collaborative Study of Membranoproliferative Glomerulonephritis Type II

描述（由申请方提供）：II型膜增生性肾小球肾炎或致密存款病（MPGNII/DDD）的特征在于电子致密物质沉积在肾脏的肾小球基底膜（GBM）内和眼睛的Bruch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，偶尔伴有视力损害的晚期合并症。在大多数MPGNII/DDD患者中，可通过低APH 50值、低Cs水平和Cs降解产物Csd的出现在血浆中记录C3连续降解导致的低补体血症。肾移植与几乎所有同种异体移植物的疾病复发相关，并且高百分比的移植最终失败。MPGNII/DDD是一种复杂的疾病。我们假设：i）其病理生理学与旁路途径（AP）C3转化酶的失调有关，这导致补体AP的不受控制的活化; 2）补体AP的不受控制的活化发生在允许的遗传背景下;和3）对GBM和布鲁赫膜的损伤发生，因为这两种膜仅具有对AP介导的补体损伤的边缘保护。我们提供了初步证据来支持这一假设，表明特定的突变和/或等位基因的因子H，因子H相关的5和Cs与MPGNII/DDD。对于两个因子H相关等位基因，AK 224和H402，我们已经完成了功能研究，证明了突变蛋白与野生型蛋白相比的差异。在这项资助中，我们将完成三个具体目标，以更详细地调查补充AP在MPGNII/DDD中的作用。具体目标是：1.具体目的i：检查几种补体相关基因中的等位基因/突变与MPGNII/DDD 2相关的假设。具体目标2：检查在具体目标中鉴定的相关等位基因/突变的假设！在功能水平上影响补体的AP 3.具体目标3：检验外源性鼠H因子（mFH）可挽救H因子缺陷小鼠（C/ft-/-）中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-/-)