Effect of Rho GTPase-regulating protein DLC1 on podocytes

• Applicant: Dr. Verena Klämbt
• Subject Area: Nephrology ; Human Genetics ; Pediatric and Adolescent Medicine
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403877094

Chronic kidney diseases represent a global health care burden. The primary causes of chronic kidney disease in children differ from those in adults. The steroid-resistant nephrotic syndrome contributes the 2nd most frequent cause of chronic kidney disease in childhood. It occurs when the renal filtration barrier is impaired due to podocyte damage. So far, no curative treatment exists. Over the last years genetic testing and the identification of single gene causes led to a paradigm shift in the understanding of the pathogenesis of the nephrotic syndrome by placing the renal podocyte at center stage. However, despite remarkable progress, many of the disease causing genes are still unknown and the disease mechanisms remain poorly understood. The main research objective of this project is to gain a better understanding of the pathophysiology of the nephrotic syndrome. To reach this goal, whole exome sequencing, which is well established in the Hildebrandt lab, will be performed using a cohort of 20 consanguineous families, 10 siblings and 500 trio families. In addition, the role of DLC1, which was recently identified as causing steroid-resistant nephrotic syndrome, will be analyzed in detail. DLC1 is a Rho regulating GTPase, important for actin-cytoskeleton organization. Its biological functions in podocytes, such as cell migration, focal adhesion, endocytosis or GTPase activity, its interaction partner and thus its role in the pathogenesis of nephrotic syndrome will be deciphered. Gain and loss of function experiments will be performed in vitro and in vivo using human podocyte cell culture and podocyte specific Dlc1 knockout mice, respectively. Finally, the ultimate goal of this study is to contribute to the development of novel treatment options for patients suffering from nephrotic syndrome.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Friedhelm Hildebrandt