Identifying novel therapeutic targets for lipotoxicity-driven kidney diseases

• Applicant: Dr. Sebastian Sewerin
• Subject Area: Nephrology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502928386

Excess circulating lipids constitute an important environmental factor in the development of complex metabolic diseases such as type 2 diabetes mellitus. Thereby, ectopic accumulation of free fatty acids causes organ dysfunction by a deleterious process termed lipotoxicity. In diabetic nephropathy as well as in some genetically-driven kidney disorders, dysregulations of lipid metabolism have been shown to occur in podocytes, postmitotic cells indispensable for the integrity of the glomerular filter. Despite these advances, the identification of promising targets for therapeutic intervention has proven challenging, revealing the need for a systematic assessment of podocyte lipotoxicity. Here, I propose to conduct a systematic study of the cellular effects of exposure to free fatty acids in podocytes, and to thereby identify novel therapeutic targets for lipotoxicity-driven kidney diseases. To this end, a comprehensive library of free fatty acids will be screened for podocyte lipotoxicity, followed by a genome-wide CRISPR-Cas9 knockout screen to identify genes implicated in lipotoxicity-mediated podocyte injury. These results will inform the study of the disease mechanism underlying a novel monogenic instance of podocyte injury for which kidney organoid technology will be employed.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Anna Greka, Ph.D.