LAMININS AND GLOMERULAR FILTRATION

 描述（由申请人提供）：本R 01修订申请是为了响应PAR-14-006“NIDDK使命（修订版）（R 01）中发现和开发疾病和病症新疗法的转化研究种子合作"而提交的。父母补助金的重点是更好地了解和确定治疗方法，皮尔逊综合征（先天性肾病综合征，具有明显的眼睛和神经缺陷）及其主要表现为孤立性先天性肾病综合征的较不严重的变体。皮尔逊综合征主要由LAMB 2（编码层粘连蛋白β2链的基因）的无效突变引起。层粘连蛋白β2是肾小球基底膜的主要组分，作为层粘连蛋白-521异源三聚体的一部分。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，但与严重得多的肾外受累是由LAMB 2中的错义突变引起的，该突变允许产生全长但有缺陷的蛋白质。虽然皮尔逊综合征的“谱系”很罕见，但LAMB 2的突变，沿着NPHS 1（nephrin）、NPHS 2（podocin）和WT 1（Wilms' tumor protein）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已经具有转化性质，但此次修订申请的目标是扩大母基金的范围，以包括直接治疗方法。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中层粘连蛋白过少所致。修订版中提出的实验将测试层粘连蛋白-521三聚体可以通过静脉输注治疗性地递送到GBM的假设，并且它们将并入GBM并恢复对肾小球滤过屏障的选择性。Lamb 2缺失小鼠和表达与人肾病综合征相关的突变形式的小鼠都将用于拟定的研究。该提案特别响应PA，因为它包括建议的合作者/顾问布拉德利霍奇斯博士的意见和提供的服务，他既是细胞外基质生物化学专家，也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导致一种新的治疗方法，用于具有明确遗传起源的明确定义的人类肾脏疾病。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经验丰富的工业合作伙伴的帮助下转化为人类患者。

 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.