FEASIBILITY OF REPAIRING GBM DEFECTS IN VIVO

体内修复 GBM 缺陷的可行性

基本信息

批准号：
8385717
负责人：
JEFFREY H MINER
金额：
$ 22.8万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385717
关键词：
Accounting Affect Agrin Albuminuria Basement membrane Binding Biological Models Blood capillaries Bone Marrow Bowman&apos s space Cell Therapy Cell Transplants Cells Collagen Collagen Type IV Congenital Nephrotic Syndrome Defect Development Diabetic Nephropathy Disease Disease model Doxycycline Endothelial Cells Endothelium Experimental Designs Extracellular Matrix Extravasation Feasibility Studies Figs - dietary Foot Process Gene Proteins Glomerulonephritis Goals Hematuria Heparan Sulfate Proteoglycan Hereditary nephritis Human Individual Infusion procedures Inherited Kidney Kidney Diseases Knowledge Laminin Membrane Biology Membrane Proteins Mus Mutation Nature Nephrotic Syndrome Pathology Patients Plasma Proteins Procedures Protein Isoforms Proteinuria Renal function Renal glomerular disease Reporting Research Sagittaria Sorting - Cell Movement Syndrome Testing Tetracyclines Time Trans-Activators Transgenes Transgenic Mice Translating Urine base capillary design enzyme replacement therapy glomerular basement membrane glomerular filtration heparin proteoglycan human disease improved in vivo laminin S mesangial cell mouse genome mouse model mutant nidogen-1 podocyte prevent programs repaired research study restoration slit diaphragm tool

项目摘要

DESCRIPTION (provided by applicant): The glomerular basement membrane (GBM) is a specialized extracellular matrix and a crucial component of the kidney's glomerular filtration barrier (GFB) between the vasculature and the urinary space. The GBM is initially co-synthesized by, and lies between, the podocytes and the glomerular endothelial cells, and it is bound by mesangial cells at the base of each capillary loop. The GBM's major components are laminin-521 (alpha5beta2gamma1), type IV collagen (the alpha3/4/5 network), nidogens-1 and -2, and the heparin sulfate proteoglycan agrin. Of these 9 components, mutations that affect 4 of them cause human kidney disease: mutations that affect the collagen IV chains cause Alport syndrome (hereditary glomerulonephritis), and those that affect laminin beta2 (LAMB2) cause Pierson syndrome/congenital nephrotic syndrome. The well-defined nature of the glomerular defects and the existence of well- characterized mouse models make these diseases especially attractive for targeted therapy. Several groups have already explored the potential for cell-based therapies aimed at replacing the missing collagen IV network in Alport mice. Although the positive effects of bone marrow and other cell transplants or infusions on progression of kidney disease seem promising, the reported effects of these procedures on the GBM's collagen IV network have been disparate and controversial. Here we propose experiments aimed at directly testing the feasibility of altering the GBM after it has matured in mouse models of Alport syndrome and Pierson syndrome/congenital nephrotic syndrome, with the goal of replacing the abnormal networks present in the mutants with the networks normally present in healthy mature glomeruli. We will use newly generated podocyte-specific reverse tetracycline transactivator transgenic mice and existing collagen IV and laminin mutant and transgenic mice to attempt to induce network restoration after GBM maturation. The results of these feasibility studies will have implications not only for treating human kidney disease, but also for our basic understanding of basement membrane biology, GBM plasticity, and cell/matrix interactions! PUBLIC HEALTH RELEVANCE: The glomerular basement membrane (GBM) is an important component of the glomerular filtration barrier that prevents the leakage of plasma proteins into the urine. Some patients with kidney disease have abnormal GBM composition. The overall goal of this proposal is to use a mouse model system to investigate whether an abnormal GBM composition can be normalized in patients and whether this will improve and/or prolong kidney function.

描述（由申请人提供）：肾小球基底膜（GBM）是一种特殊的细胞外基质，也是血管系统和泌尿道之间的肾脏肾小球滤过屏障（GFB）的重要组成部分。 GBM 最初由足细胞和肾小球内皮细胞共同合成，并位于足细胞和肾小球内皮细胞之间，并与每个毛细血管环底部的系膜细胞结合。 GBM 的主要成分是层粘连蛋白-521 (alpha5beta2gamma1)、IV 型胶原蛋白（alpha3/4/5 网络）、nidogens-1 和 -2 以及硫酸肝素蛋白聚糖集聚蛋白。在这 9 种成分中，影响其中 4 种的突变会导致人类肾脏疾病：影响 IV 型胶原蛋白链的突变会导致 Alport 综合征（遗传性肾小球肾炎），影响层粘连蛋白 beta2 (LAMB2) 的突变会导致皮尔森综合征/先天性肾病综合征。肾小球缺陷的明确性质和特征明确的小鼠模型的存在使得这些疾病对于靶向治疗特别有吸引力。一些研究小组已经探索了细胞疗法的潜力，旨在替代 Alport 小鼠中缺失的 IV 型胶原蛋白网络。尽管骨髓和其他细胞移植或输注对肾脏疾病进展的积极影响似乎很有希望，但这些手术对 GBM 的 IV 型胶原蛋白网络的影响报道却各不相同且存在争议。在这里，我们提出了一些实验，旨在直接测试在阿尔波特综合征和皮尔森综合征/先天性肾病综合征小鼠模型中改变GBM成熟后的可行性，目的是用正常存在于突变体中的网络取代突变体中存在的异常网络。健康成熟的肾小球。我们将使用新生成的足细胞特异性逆四环素反式激活剂转基因小鼠和现有的 IV 型胶原蛋白和层粘连蛋白突变体和转基因小鼠来尝试在 GBM 成熟后诱导网络恢复。这些可行性研究的结果不仅对治疗人类肾脏疾病产生影响，而且对我们对基底膜生物学、GBM 可塑性和细胞/基质相互作用的基本理解产生影响！公共卫生相关性：肾小球基底膜 (GBM) 是肾小球滤过屏障的重要组成部分，可防止血浆蛋白渗漏到尿液中。一些肾病患者的 GBM 成分异常。该提案的总体目标是使用小鼠模型系统来研究患者的异常 GBM 成分是否可以正常化，以及这是否会改善和/或延长肾功能。