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Using Drosophila melanogaster to study hereditary kidney diseases – NEPHROFLY

Submission summary

Next-generation sequencing technologies have enabled rapid identification of many genes contributing to human disease. One of the major difficulties with this new approach is to prove pathogenicity of a given variant, making functional validation a top priority-issue in human genetics. The aim of this proposal is to establish Drosophila as a functional model for human genetic diseases of the kidney.
One of the most important functions of the kidney is blood filtration, which occurs in the glomerulus. A crucial structure in filtration is the slit diaphragm, which is formed between interdigitating foot processes of the podocytes and functions as a the major determinant of charge selectivity for serum proteins. Proteins that have made through the glomerular filter are for the most part reabsorbed by the proximal tubular (PT) cells. To perform this task, PT cells possess a dense brush border on their apical surfaces and a dedicated protein uptake pathway with the megalin/cubilin complex as the main protein receptor. This pathway is also operating in podocytes, but its significance in this cell type is less clear. Defects in podocytes and PT cells cause the loss of proteins into the urine, also termed proteinuria. Studies of rare hereditary causes of proteinuria have led to the identification of the molecular components of podocyte foot processes and slit diaphragms. With similar efficiency, gene identification for proximal tubular dysfunction (also called Fanconi syndrome) has uncovered important endocytic proteins. Interestingly, some patients with Fanconi syndrome present with unusually high ranges of proteinuria with biopsies showing glomerular lesions, suggesting that podocytes might also be affected.
Recently, a special cell type in Drosophila, termed nephrocyte, has been shown to possess the molecular machineries for both slit diaphragm-mediated filtration and megalin/cubilin-based endocytic uptake. It is therefore an ideal model to study the pathogenesis of proteinuria. This is particularly important in light of the fact that both mammalian podocytes and PT cells are difficult to cultivate in a differentiated state. Our work program will move from a basic characterization of Drosophila nephrocyte to the establishment of bona fide model for Dent’s disease. Dent's disease is a hereditary defect in the endocytosis pathway of PT cells and, presumably, podocytes. This model will be used to study pathogenetic mechanisms of proteinuria. The focus will be on endocytic defects, which we hypothesize to be a significant cause of proteinuria forms involving both podocytes and PT cells. Further, an important task will be to perform whole exome sequencing on selected cohorts of patients with proteinuria and, subsequently, use Drosophila for candidate disease gene validation.
The partnership between the applicant and the Imagine Institute is an ideal combination to fulfill this task. While the applicant has extensive experience with both kidney and Drosophila research, the newly opened Imagine house various groups working on human genetic diseases of the kidney but also other organ systems. Therefore, the ultimate goal of this proposal is to prove that Drosophila can contribute to decision-making in human genetics by providing an efficient pipeline for assessing the pathogenicity of genome variations.

Project coordination

Matias SIMONS (Laboratory of Epithelial Biology and Disease)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Institute Imagine/INSERM Laboratory of Epithelial Biology and Disease

Help of the ANR 549,926 euros
Beginning and duration of the scientific project: May 2015 - 48 Months

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