LAMININS AND GLOMERULAR FILTRATION

点击翻译按钮获取中文摘要

 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.