Address of the institution:
The majority of cases of steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) in childhood and adolescence is caused by mutations in single genes. While the probability of single-gene causes of FSGS declines with age there is a clear role for genetic susceptibility also in sporadic forms of FSGS in adulthood. Although the past two decades have witnessed spectacular breakthroughs in the understanding of the genetic basis of SRNS/FSGS, almost 20 years after the description of gene defects in the genes encoding for the slit diaphragm proteins nephrin and podocin the ultimate steps leading to SRNS/FSGS are far from being understood. The overall aim of this research project is to elucidate the pathogenic mechanisms of podocyte foot process effacement (and SRNS) and progressive loss of podocytes (and FSGS) in patients with NPHS2 (podocin) mutations as well as in situations of alterations of slit diaphragm signaling in general. The project follows a three-pronged approach and is based on breakthrough technical achievements that were possible over the past few years. We will elucidate how human pathogenic mutations impact on podocyte signaling, the integrity of the slit diaphragm and proteostasis mechanisms, analyze how Nphs2 mutations impact on mechano-biology of the podocyte with a specific view on how mechanosensor signaling influences cell behaviour and cell fate decisions, cytoskeletal regulation, and genetic programs of phenotypic plasticity, and study how subtle genetic alterations (heterozygous or combined heterozygous mutations of the Nphs2 gene) may predispose podocytes to injury, FSGS and renal failure.