LAMININS AND GLOMERULAR FILTRATION

层粘连蛋白和肾小球滤过

基本信息

批准号：
9038021
负责人：
JEFFREY H MINER
金额：
$ 10.29万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038021
关键词：
Accounting Affect Albuminuria Amino Acids Animal Model Animals Applications Grants Basement membrane Biochemistry Biodistribution Blood Circulation Child Collaborations Congenital Nephrotic Syndrome Data Defect Development Diffuse Disease Ensure Extracellular Matrix Eye Filtration Fluorescein-5-isothiocyanate Foot Process Funding Genes Genetic Goals Health Heterogeneity Homologous Gene Human Industry Intravenous Intravenous infusion procedures Kidney Kidney Diseases Knockout Mice Label Laboratories Laminin Lead Length Life Link Longevity Maintenance Miosis disorder Missense Mutation Mission Mus Mutant Strains Mice Mutation NPHS2 protein Nature Nephroblastoma Nephrotic Syndrome Nervous system structure Neurologic Outcome Study Pathogenesis Patients Phenotype Play Proteins Rare Diseases Recombinants Renal glomerular disease Replacement Therapy Reporting Role Sclerosis Services Specificity Stress Symptoms Syndrome Testing Therapeutic Translating Translational Research Translations Variant WT1 gene experience glomerular basement membrane glomerular filtration human disease improved mouse model mutant nephrin neuromuscular system novel therapeutic intervention null mutation overexpression parent grant podocyte preclinical study protein misfolding public health relevance research study response small molecule success

项目摘要

DESCRIPTION (provided by applicant): This R01 revision application is being submitted in response to PAR-14-006, "Seeding Collaborations for Translational Research to Discover and Develop New Therapies for Diseases and Conditions within NIDDK's Mission (Revisions) (R01)". The parent grant is focused on gaining a better understanding of, and identifying therapeutics for, Pierson syndrome (congenital nephrotic syndrome with distinct eye and neurological defects) and its less severe variants presenting primarily with isolated congenital nephrotic syndrome. Pierson syndrome is caused primarily by null mutations in LAMB2, the gene that encodes the laminin β2 chain. Laminin β2 is a major component of the glomerular basement membrane as part of the laminin-521 heterotrimer. A less severe variant of Pierson syndrome that includes the congenital nephrotic syndrome aspect but with much less severe extrarenal involvement is caused by missense mutations in LAMB2 that allow a full length but defective protein to be produced. Although the "spectrum" of Pierson syndrome is rare, mutations in LAMB2, along with those in NPHS1 (nephrin), NPHS2 (podocin), and WT1 (Wilms' tumor protein), account for two-thirds of cases of nephrotic syndrome in the first year of life. Although Aims 1 and 2 of the parent grant are already translational in nature, the goal of this revision application is to expand the scope of the parent grant to include a direct therapeutic approach. The PI's studies have shown that the nephrotic syndrome caused by laminin β2 mutations results from there being too little laminin in the GBM. The experiments proposed in the revision will test the hypothesis that laminin-521 trimers can be therapeutically delivered to the GBM by intravenous infusion, and that they will incorporate into the GBM and restore selectivity to the glomerular filtration barrier. Both Lamb2 null mice and those expressing the mutant forms linked to human nephrotic syndrome will be used in the proposed studies. This proposal is especially responsive to the PA because it includes input from and services provided by a proposed collaborator/consultant, Dr. Bradley Hodges, who is both an expert in extracellular matrix biochemistry and has been involved in the successful development of companies that are using large matrix molecules as therapies for human disease. The outcome of these studies could lead to a new therapeutic approach for a well-defined human kidney disease with a clear genetic origin. The collaboration between Miner (PI) and Hodges (Collaborator/Consultant) brings together complementary expertise and backgrounds (academic and biotech/industry) and ensures that success in these preclinical studies will be carried forward for translation to human patients with the help of an experienced industrial partner.

描述（由申请人提供）：此 R01 修订申请是为了响应 PAR-14-006“在 NIDDK 使命（修订）（R01）范围内为发现和开发疾病和病症的新疗法而开展转化研究种子合作”而提交。家长资助的重点是更好地了解皮尔森综合征（先天性肾病综合征，具有明显的眼睛和神经系统症状）并确定治疗方法。缺陷）及其主要表现为孤立性先天性肾病综合征的不太严重的变异主要是由 LAMB2 的无效突变引起的，该基因编码层粘连蛋白 β2 链，是肾小球基底膜的主要组成部分。层粘连蛋白-521 异三聚体。皮尔逊综合征的一种不太严重的变异，包括先天性肾病综合征方面，但肾外受累的严重程度要低得多，是由错义突变引起的。 LAMB2 允许产生全长但有缺陷的蛋白质，尽管皮尔森综合征的“谱”很罕见，但 LAMB2 以及 NPHS1（肾病蛋白）、NPHS2（podocin）和 WT1（维尔姆斯肿瘤蛋白）中的突变。，占出生后第一年肾病综合征病例的三分之二。虽然母基金的目标 1 和 2 本质上已经是转化性的，但本次修订的目标。申请的目的是扩大母基金的范围，将直接治疗方法纳入其中。 PI 的研究表明，由层粘连蛋白 β2 突变引起的肾病综合征是由于 GBM 中层粘连蛋白太少所致。修订中提出的实验将进行测试。层粘连蛋白 521 三聚体可以通过静脉输注治疗性地递送至 GBM，并且它们将融入 GBM 并恢复对肾小球滤过屏障的选择性。 Lamb2 缺失小鼠和表达与人类肾病综合征相关的突变形式的小鼠将用于拟议的研究，因为它包括拟议的合作者/顾问 Bradley Hodges 博士的意见和服务。他既是细胞外基质生物化学方面的专家，又参与了使用大基质分子作为人类疾病疗法的公司的成功开发，这些研究的结果可能会为明确的人类肾脏带来一种新的治疗方法。疾病有明确的Miner (PI) 和 Hodges（合作者/顾问）之间的合作汇集了互补的专业知识和背景（学术和生物技术/行业），并确保这些临床前研究的成功将在帮助下转化为人类患者。经验丰富的工业合作伙伴。