LAMININS AND GLOMERULAR FILTRATION

层粘连蛋白和肾小球滤过

基本信息

批准号：
8723802
负责人：
JEFFREY H MINER
金额：
$ 33.06万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723802
关键词：
Affect Agrin Albumins Albuminuria Amino Acids Applications Grants Basement membrane Cell Culture Techniques Cells Child Chloride Channels Collagen Type IV Congenital Nephrotic Syndrome Congenital neurologic anomalies Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Defect Diffuse Extracellular Matrix Filtration Foot Process Funding Genetic Goals Health Heparan Sulfate Proteoglycan Heterogeneity Homologous Gene Human In Vitro Kidney Kidney Diseases Kidney Failure Laboratories Laminin Lead Libraries Maintenance Membrane Biology Membrane Structure and Function Methods Miosis disorder Missense Mutation Mus Mutation Nephrotic Syndrome Nervous system structure Neurologic Nidogen Patients Pharmaceutical Preparations Plasma Proteins Play Proteinuria Rare Diseases Renal glomerular disease Reporting Robotics Role Sclerosis Specificity Symptoms Syndrome Testing Transgenic Mice Translating glomerular basement membrane glomerular filtration high throughput screening improved in vivo insight interest laminin S laminin-1 laminin-5 mouse model mutant neuromuscular system null mutation overexpression podocyte polymerization public health relevance small molecule small molecule libraries trafficking

项目摘要

DESCRIPTION (provided by applicant): Kidney disease is worldwide health problem that is becoming increasingly prevalent. Primary glomerular disease, both acquired and genetic, represents a significant proportion of these cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged and leaky to plasma proteins. Our focus over the last sixteen years has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the filtration barrier. The GBM contains laminin, collagen IV, nidogen, and the heparan sulfate proteoglycan agrin. Our studies of mice lacking the laminin beta2 chain suggests that the GBM itself serves as a barrier to albumin and protects podocytes from the injurious effects of plasma proteins, as mice lacking laminin beta2 develop nephrotic syndrome and renal failure. Mutations in human LAMB2 have also been shown to cause kidney disease; null mutations cause Pierson syndrome (congenital nephrotic syndrome with ocular and nervous system abnormalities), whereas missense mutations cause congenital nephrotic syndrome with less severe extrarenal manifestations. Our recent studies have shown that some of these missense mutations impair secretion of laminin-521 into the GBM, and that increased secretion of even mutant forms could be beneficial for patients carrying such mutations. The focus of this proposal is to find methods to ameliorate kidney disease in patients with GBM defects due to laminin abnormalities and to better understand the role of laminin polymerization in GBM structure and function. To accomplish this, we will 1) perform high throughput screens of drug libraries to find compounds that can promote secretion of mutant LAMB2 chains in vitro; 2) test these compounds in vivo in our mouse models expressing mutant laminin beta2 chains to look for improved secretion and an improved filtration barrier; and 3) characterize activity and function of a human LAMB2 mutation that affects laminin polymerization. The results of these studies will provide important new insights into laminin and basement membrane biology and lead to potential therapies for human glomerular disease involving GBM defects.

描述（由申请人提供）：肾脏疾病是一个日益普遍的世界性健康问题。原发性肾小球疾病，包括获得性和遗传性，占这些病例的很大一部分。我们有兴趣了解肾小球滤过屏障的构成以及它如何受损和渗漏血浆蛋白。过去十六年我们的重点是研究肾小球基底膜 (GBM) 的组成和功能，肾小球基底膜是一种特殊的细胞外基质，是滤过屏障的组成部分。 GBM 含有层粘连蛋白、IV 型胶原蛋白、巢蛋白和硫酸乙酰肝素蛋白聚糖集聚蛋白。我们对缺乏层粘连蛋白β2链的小鼠的研究表明，GBM本身可以作为白蛋白的屏障，并保护足细胞免受血浆蛋白的有害影响，因为缺乏层粘连蛋白β2的小鼠会出现肾病综合征和肾衰竭。人类 LAMB2 突变也被证明会导致肾脏疾病；无效突变会导致皮尔森综合征（伴有眼部和神经系统异常的先天性肾病综合征），而错义突变会导致肾外表现较轻的先天性肾病综合征。我们最近的研究表明，其中一些错义突变会损害层粘连蛋白 521 向 GBM 的分泌，甚至突变形式的分泌增加可能对携带此类突变的患者有益。该提案的重点是寻找改善因层粘连蛋白异常而导致 GBM 缺陷的患者的肾脏疾病的方法，并更好地了解层粘连蛋白聚合在 GBM 结构和功能中的作用。为了实现这一目标，我们将1）对药物库进行高通量筛选，以找到可以在体外促进突变LAMB2链分泌的化合物； 2) 在表达突变层粘连蛋白β2链的小鼠模型中体内测试这些化合物，以寻找改善的分泌和改善的过滤屏障； 3) 表征影响层粘连蛋白聚合的人类 LAMB2 突变的活性和功能。这些研究的结果将为层粘连蛋白和基底膜生物学提供重要的新见解，并为涉及 GBM 缺陷的人类肾小球疾病提供潜在的治疗方法。