Transcriptional programs governed by YAP and TAZ and their nuclear control mechanisms in FSGS

The transcriptional regulators YAP and TAZ, downstream targets of Hippo signaling, are central for the homeostasis and survival of podocytes and as such indispensable to maintaining glomerular architecture and function. Remarkably, both hyperactivity YAP and TAZ, as well as loss of YAP and TAZ activity, are associated with podocyte damage and glomerular disease, and tightly controlled regulatory mechanisms are required to keep YAP and TAZ activity in balance. Fundamental studies revealed that YAP and TAZ act downstream of various pathways and biological processes receiving a plethora of inputs. While there appears to be a huge diversity of tissue and cell-specific mechanisms and functions to keep YAP/TAZ at check or to unleash their transcriptional functions, this converges in the nuclear shuttling of YAP and TAZ, their binding to transcription factors, the association with enhancer elements and their regulation through posttranslational modifications.

The overarching aim of our project is to uncover the nuclear functions and mechanisms of how YAP and TAZ activate overlapping and distinct transcriptional programs specifically in podocytes that can either promote injury or support survival. Specifically, we will investigate interchangeable and unique functions of YAP and TAZ and their effects on transcriptional programs involved in FSGS, study the transcriptional machinery orchestrated by YAP and TAZ and how nucleoporins regulate the dynamics of YAP/TAZ nuclear shuttling in podocytes and analyze the role of YAP and TAZ signaling in response to changes in glomerular hemodynamics. With this, we aim to discover novel ways to rewire podocytes’ YAP and/or TAZ signaling and to pave the way for novel therapeutic strategies for FSGS.