Disruption of the nuclear pore protein 93 in podocyte injury

• Applicant: Privatdozentin Dr. Daniela Anne Braun
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527981127

In previous studies, we have identified recessive mutations in NUP93 and six other genes that encode functionally-related structural proteins of the nuclear pore complex (NPC), a gated channel across the nuclear envelope of eukaryotic cells, as inherited causes of chronic glomerular kidney disease in paediatric patients. Surprisingly, despite the essential cellular function, ubiquitous expression, and high evolutionary conservation of NPCs, affected patients mostly presented with a kidney-specific phenotype, thus indicating a specific vulnerability of glomerular epithelial cells for disruption of NPCs. As specific therapies for most types of glomerular disease are lacking, further insights into the molecular pathogenesis are urgently need to improve therapy for affected patients. In preliminary studies, we have developed a mouse model with podocyte-specific knockout of the Nup93 gene that recapitulates the human phenotype of progressive glomerular kidney disease. In this proposal, we aim to elucidate the molecular mechanisms of podocyte injury due to NUP93 depletion. Therefore, we will utilize nephrocytes of Drosophila melanogaster as a model system to study the impact of pathogenic NUP93 mutations on nuclear pores, nuclear morphology, nuclear transport, and their consequences on the nephrocyte’s cytoskeleton and slit diaphragm. In the second aim, we will define the specific transcriptional alterations that drive podocyte injury and glomerular disease upon knockout of the Nup93 in mice by using single-nucleus RNA sequencing. Finally, we will implement a kidney organoid model from human induced pluripotent stem cells to study the impact of NUP93 mutations and pharmacological modulation of nuclear transport on podocyte development and differentiation. Further, newly identified molecular injury pattern will be validated in this human model system and will be tested as potential targets for therapy. In summary, our aim is to refine the role of NUP93 in glomerular development and disease and to understand the particular vulnerability of podocytes, specialized glomerular epithelial cells, to alterations in nuclear pores.

• DFG Programme: Research Grants