Urinary Biomarkers in Murine MPGN

小鼠 MPGN 中的尿液生物标志物

• 批准号: 6962745
• 负责人: MICHAEL C BRAUN
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6962745
• 关键词: alternative complement pathway; beta globulin; biomarker; blood proteins; complement; complement inhibitors; complement pathway; disease /disorder model; enzyme linked immunosorbent assay; genetic strain; genetic transcription; immunocytochemistry; in situ hybridization; kidney; laboratory mouse; liquid chromatography mass spectrometry; membranous glomerulonephritis; pathologic process; polymerase chain reaction; protein quantitation /detection; protein structure function; proteomics; urinalysis; western blottings

DESCRIPTION (provided by applicant): Membranoproliferative glomerulonephritis Type II (MPGN II) is an uncommon form of chronic renal disease primarily effecting older children and adolescents. It is defined histologically by the presence of electron dense deposits within the lamina densa of the glomerular basement membrane. While MPGN II is associated with both systemic hypocomplementemia and local deposition of complement components in the glomerulus, the pathogenic mechanisms that mediate renal injury in this disease remain undefined. Recently it has been demonstrated that mice deficient in Factor H, a critical regulator of the alternative complement pathway, develop chronic glomerular disease identical to that seen in humans with MPGN II. This proposal is designed to identify urinary biomarkers of renal injury in this model system. Using advanced proteomic tools, differential expression of urinary proteins will be analyzed comparing urine from mice deficient in Factor H to urine from control mice. Samples will be analyzed temporally to characterize progressive alterations in patterns of urinary protein expression. Proteins that are differentially expressed will then be characterized at multiple levels using immunohistochemically, Western Blot, and quantitative RT-PCR. The primary goals of this proposal are two fold, first to identify potential biomarkers specific for MPGN II, and second to gain insight into the pathogenic mechanisms by which complement activation mediates renal injury in a biologically relevant model of human disease. Findings from these studies have the potential to have a significant impact on our understanding of the basic mechanisms by which complement activation contributes to renal injury not only in MPGN II, but also in other complement dependent nephritidies including post-infectious glomerular nephritis and lupus nephritis.

描述（由申请人提供）：II型膜增生性肾小球肾炎（MPGN II）是一种罕见的慢性肾脏疾病，主要影响年龄较大的儿童和青少年。在组织学上，肾小球基底膜致密层内存在电子致密沉积物。虽然MPGN II与系统性低补体血症和肾小球中补体成分的局部沉积有关，但在这种疾病中介导肾损伤的致病机制仍不明确。最近已经证明，缺乏因子H（替代补体途径的关键调节剂）的小鼠发展慢性肾小球疾病，与患有MPGN II的人类中所见的相同。该提议旨在确定该模型系统中肾损伤的尿生物标志物。使用先进的蛋白质组学工具，将H因子缺陷小鼠的尿液与对照小鼠的尿液进行比较，分析尿蛋白的差异表达。将对样本进行时间分析，以表征尿蛋白表达模式的进行性变化。差异表达的蛋白质随后将使用免疫化学、蛋白质印迹和定量RT-PCR在多个水平进行表征。该提案的主要目标有两个方面，首先是确定MPGN II特异性的潜在生物标志物，其次是深入了解补体激活介导人类疾病生物学相关模型中肾损伤的致病机制。这些研究的结果有可能对我们理解补体激活不仅在MPGN II中导致肾损伤，而且在其他补体依赖性肾炎包括感染后肾小球肾炎和狼疮性肾炎中导致肾损伤的基本机制产生重大影响。