Central to the vectorial transport function of renal epithelium is the polarized distribution of surface membrane proteins in renal epithelial cells. Recent evidence indicates that the spectrin based cortical cytoskeleton, which is often associated with certain integral membrane proteins, is also highly polarized, and may play a fundamental role in maintaining and guiding topographic membrane assembly. The overall goal of the proposed studies will be to understand how the cortical cytoskeleton achieves its polarized distribution, and the relationship of this process to the sorting of basolaterally restricted integral membrane proteins such as Na,K-ATPase and E-cadherin. Specifically, research will focus on how perturbation of the factors that target the assembly of the spectrin skeleton to the lateral margins of kidney epithelial cells regulate its interactions with other integral membrane proteins such as E-cadherin and Na,K-ATPase affect in vivo renal development, function, and the response of the kidney to pathologic stress. Specific proteins to be examined include the erythroid-like and non-erythroid isoforms of spectrin (fodrin), ankyrin, adducin, and protein 4.1, E-cadherin, alpha-catenin, as well as novel proteins that interact with renal spectrin. The interaction between these proteins will be measured by sensitive genetic and biochemical assays, and their role in vivo will be gauged by constructing transgenic mice with specific cytoskeletal mutations. Since many cytoskeletal mutations have been found in cell culture models to act in a dominant negative fashion, it is anticipated that these studies will guide our search for renal diseases in which membrane cytoskeletal dysfunction plays an etiologic role.
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