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Characterization of novel proteins interacting with cubilin and their role in proximal tubular endocytosis

Objective

Megalin and cubilin mediated endocytosis at the apical pole of proximal tubule epithelial cells constitute a major route for renal retrieval of several essential glomerular filtrate solutes such as proteins vitamins and calcium. Pathophysiological signific ance of these receptors is supported by the finding of low-molecular weight proteinuria in megalin knockout mice and in dogs that bear inherited disorder of cubilin intracellular trafficking although the structure of cubilin is normal. Recently two protein s possibly responsible for cubilin trafficking has been identified: amnionless and cubilin-binding protein. The aim of the study is a closer characterization of those proteins and their role in megalin/cubilin mediated endocytosis as well as disclosure of possible target molecules/interactions for pharmacological intervention preventing reabsorption of toxic molecules in the proximal tubule. The studies include identification of the proteins involved, their purification and analysis, characterization of the ir interactions and subcellular distribution as well as functional studies by molecular biology approaches and pharmacological targeting. The intimate knowledge of the molecular interactions involved in the endocytic process that will be gained from the pr esent study are essential for the development of new therapeutic approaches in nephrology that involve modulation of cubilin and megalin expression/function in order to prevent or attenuate tubular uptake of deleterious substances. The project is the furth er initiative of the applicant in his scientific training, which started in Department of Biochemistry in Poland and was followed by stay in the Department of Cell Biology in Denmark. During the stay in INSERM U538 (Membrane Traffic in Epithelial Cells) th e applicant will be provided with thorough training in cell culture and molecular biology techniques.

Call for proposal

FP6-2004-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
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101, Rue De Tolbiac
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France