Epithelial biology and disease
Pathophysiology of renal proximal tubular cells
Epithelial cells of the proximal tubules have a very active endolysosomal system, and this is because its main task is to reabsorb virtually all the proteins that are filtered by the glomerulus. For this, the apical brush borders are equipped with a dedicated protein uptake pathway, involving the multiligand receptors Megalin and Cubilin. Our recent research in Drosophila has introduced a novel mechanism for the control of apical protein uptake (Gleixner et al., 2014). Our findings propose that lysosomal mTOR signaling - a major nutrient sensing pathway that controls metabolic decisions from the lysosomal surface - regulates the expression of Megalin as well as the morphogenesis of the apical surface. Therefore, we are studying how protein and lipid ligands from the tubular lumen can amplify a cycle of endocytosis and lysosome-to-nucleus signaling to satisfy the high metabolic needs of proximal tubular cells. We are also studying several proximal tubulopathies with downregulated receptor-mediated uptake (e.g. cystinosis, Dent’s disease, MODY1, Imerslund-Gräsbeck disease). Our main experimental model is the Drosophila nephrocyte that shares strong similarities with mammalian podocyte and proximal tubular cells. In addition, we are using mice and reprogrammed renal epithelial cells.
Phenotypic consequences of proton pump dysfunction
Another line of research deals with the functional characterization of the accessory V-ATPase subunit, ATP6AP2 (also known as the (pro)renin receptor). Our results suggest that this protein participates in the assembly of the V-ATPase complex in the endoplasmic reticulum (Rujano, Cannata Serio et al., 2017). We are are addressing the role of ATP6AP2 and the V-ATPase in autophagy, various signaling pathways (PCP, Wnt, Notch, mTOR etc.) as well as human genetic diseases (Hermle et al, 2013; Trepiccione et al, 2016; Rujano, Cannata Serio et al., 2017; Guida et al, 2018).
Drosophila as a tool in human genetics
The understanding of human genetic diseases has been greatly improved by novel techniques, such as next generation sequencing, allowing the complete genotyping of vast numbers of affected individuals and their relatives. Moreover, novel genome editing methods and reprogramming of patient-derived cells have enhanced the possibilities for functional follow-up studies. However, the evaluation of the pathogenicity of genetic variants remains a major bottleneck, because the human genome still lacks important functional gene information. An important goal of the lab is to employ the Drosophila model as an innovative toolkit for the rapid identification of novel genes for hereditary diseases, particularly in the area of kidney disease (Goncalves et al, 2018; Lovric, Goncalves et al, 2017).