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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Yale University
New Haven
United States
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Biswas, Purba; Zhang, Jin; Schoenfeld, Jonathan D et al. (2005) Identification of the regions of PECAM-1 involved in beta- and gamma-catenin associations. Biochem Biophys Res Commun 329:1225-33
Payne, Geoffrey W; Madri, Joseph A; Sessa, William C et al. (2004) Histamine inhibits conducted vasodilation through endothelium-derived NO production in arterioles of mouse skeletal muscle. FASEB J 18:280-6
Ilan, Neta; Tucker, Adeline; Madri, Joseph A (2003) Vascular endothelial growth factor expression, beta-catenin tyrosine phosphorylation, and endothelial proliferative behavior: a pathway for transformation? Lab Invest 83:1105-15
Gratzinger, Dita; Barreuther, Mark; Madri, Joseph A (2003) Platelet-endothelial cell adhesion molecule-1 modulates endothelial migration through its immunoreceptor tyrosine-based inhibitory motif. Biochem Biophys Res Commun 301:243-9
Siddhanta, Anirban; Radulescu, Andreea; Stankewich, Michael C et al. (2003) Fragmentation of the Golgi apparatus. A role for beta III spectrin and synthesis of phosphatidylinositol 4,5-bisphosphate. J Biol Chem 278:1957-65
Colegio, Oscar R; Van Itallie, Christina; Rahner, Christoph et al. (2003) Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. Am J Physiol Cell Physiol 284:C1346-54
Biswas, Purba; Canosa, Sandra; Schoenfeld, Jonathan et al. (2003) PECAM-1 promotes beta-catenin accumulation and stimulates endothelial cell proliferation. Biochem Biophys Res Commun 303:212-8
Madri, Joseph A (2003) The evolving roles of cell surface proteases in health and disease: implications for developmental, adaptive, inflammatory, and neoplastic processes. Curr Top Dev Biol 54:391-410
Colegio, Oscar R; Van Itallie, Christina M; McCrea, Heather J et al. (2002) Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol 283:C142-7
Curristin, Sheila M; Cao, Anjun; Stewart, William B et al. (2002) Disrupted synaptic development in the hypoxic newborn brain. Proc Natl Acad Sci U S A 99:15729-34

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