The Role of Interleukin-15 Receptor-alpha Variants in the Pathogenesis of FSGS

摘要

ABSTRACT Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic diagnosis characterized by steroid resistant nephrotic syndrome (NS), focal scarring of the glomerular capillary tuft and rapid progression to end stage kidney disease (ESKD). The incidence of FSGS has increased more than 10-fold over the past three decades and the disease is highly prevalent in the African Americans (AA) population. Indeed, AAs account for 40% of all cases of ESKD due to FSGS despite comprising only 13% of the general population. FSGS is now the most common primary glomerular disorder causing ESKD. A characteristic feature of the disease is a reduced number of glomerular podocytes. As a result, podocytes are thought to play a pivotal role in the pathogenesis of FSGS. The study of familial forms of FSGS has provided key insights into the disease process. These studies have identified mutations in over 30 genes that are enriched in glomerular podocytes. Mutations in these genes are rare in AAs despite the high risk for progression to ESKD in the AA population. Our laboratory has collected over 30 AA kindreds with autosomal dominant FSGS. Using this unique resource, I have identified a rare heterozygous missense variant in the interleukin-15 receptor-α (IL-15RαK47R) as the only variant that segregates with the disease in an AA kindred with autosomal dominant FSGS. The variant occurs within the high-affinity “sushi” ligand binding domain of the receptor and is predicted to be damaging by SIFT and polyphen analyses. In support of a damaging effect of the mutation, we found that the IL-15RαK47R point mutation impairs IL-15-induced prosuvival signaling. Based on these preliminary data, I hypothesize that the IL-15RαK47R is a hypomorphic, loss-of-function variant that promotes impaired prosurvival signaling, resulting in podocyte apoptosis. To investigate this hypothesis, 3 specific aims are proposed: 1. Determine the effect of the IL-15Rα K47R variant on podocyte pro-survival signaling 2. Characterize the renal phenotype of the IL-15Rα-deficient mouse, and 3. Determine the prevalence of rare variants in IL-15Rα in our cohort of AA patients with FSGS. The proposed experiments will generate insights into the molecular pathogenesis of FSGS and may uncover novel therapeutic targets. Over the term of this award, I hope to develop new skills in human glomerular disease modeling in mice and to generate the data necessary for submission of an independent investigator award focused on defining the molecular pathogenesis of FSGS. My mentor for this proposal, Dr. Robert Spurney, is a leader in the field of cell biology and whole animal modeling and has extensive experience as a research mentor. Moreover, my mentor team, my experience in biochemistry and Nephrology, and the unique training environment of Duke University uniquely positions me to achieve the scientific objectives outlined in this proposal.