LAMININS AND GLOMERULAR FILTRATION

层粘连蛋白和肾小球滤过

基本信息

批准号：
9348633
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348633
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 Impairment 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 Preclinical Drug Evaluation Proteinuria Rare Diseases Renal glomerular disease Reporting Robotics Role Sclerosis Specificity Symptoms Syndrome Testing Transgenic Mice Translating glomerular basement membrane glomerular filtration glomerular function high throughput screening improved in vivo insight interest laminin A laminin S laminin alpha5 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）：肾脏疾病是越来越普遍的全球健康问题。原发性肾小球疾病均获得遗传和遗传，代表着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，以及它如何损坏和对等离子体蛋白的漏水。在过去的十六年中，我们的重点是研究肾小球基底膜（GBM）的组成和功能，这是一种专门的细胞外基质，是过滤屏障的组成部分。 GBM含有层粘连蛋白，胶原蛋白IV，Nidogen和硫酸乙酰肝素蛋白聚糖Agrin。我们对缺乏层粘连蛋白β2链的小鼠的研究表明，GBM本身是白蛋白的障碍，并保护足细胞免受血浆蛋白的有害作用，因为缺乏粘贴蛋白β2的小鼠会产生肾病综合征和肾衰竭。人Lamb2中的突变也已显示出引起肾脏疾病。无效突变引起皮尔森综合征（先天性肾病综合征，眼和神经系统异常），而错义突变会导致先天性肾病综合征，其外部表现不太严重。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对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。该提案的重点是找到因粘层蛋白异常引起的GBM缺陷患者改善肾脏疾病的方法，并更好地了解层粘连蛋白聚合在GBM结构和功能中的作用。为此，我们将1）执行药物文库的高吞吐量筛选，以找到可以在体外促进突变兰布2链的分泌的化合物； 2）在表达突变层粘连蛋白β2链的小鼠模型中测试这些化合物，以寻求改进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缺陷的人肾小球疾病提供潜在的疗法。