We have developed a mouse model deficient in Actn4, the murine homolog of the human focal segmental glomerulosclerosis gene ACTN4. These Actn4-/- mice develop proteinuria, abnormal glomerular podocyte morphology, and progressive kidney failure. Leukocyte chemotaxis, a sensitive indicator of cytoskeletal function, is altered in these mutant mice. We propose to use this model to better understand the role of Actn4-/-, with a particular focus on cell-matrix interactions and cell motility. We will: 1. Perform detailed characterization of the Actn4-/- and Actn4 mouse phenotypes. We will define the natural history of the phenotypic effect of this mutation. We will breed mice onto pure backgrounds to minimize Actn4-independent variability in the phenotype. We will characterize kidneys from these mice at histologic, biochemical, and protein expression levels. We will characterize mutant embryos and neonates in order to define the cause of increased perinatal mortality we observe in Actn4-/- mice. 2. Examine the effects of alpha-actinin-4 deficiency on cell adhesion and movement. We will assess the role of integrins in mediating altered leukocyte motility. We will examine the role of PI 3- kinase signaling in mediating this behavior. We will extend these experiments to other cell types, specifically, fibroblasts and podocytes. We will also examine the effect of alpha-actinin-4 deficiency cytoskeletal and growth properties of these cells. 3. Develop a """"""""floxed"""""""" Actn4 allele in order to create a podocyte-specific Actn4 knockout mouse. This model will allow us to dissect the podocyte-specific contribution to the Actn4-/- phenotype and facilitate studies of the role of Actn4 in other cell types.
| Henderson, J M; Al-Waheeb, S; Weins, A et al. (2008) Mice with altered alpha-actinin-4 expression have distinct morphologic patterns of glomerular disease. Kidney Int 73:741-50 |
| Dandapani, Savita V; Sugimoto, Hikaru; Matthews, Benjamin D et al. (2007) Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem 282:467-77 |
