# Hippo-YAP in podocyte health and disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $526,542

## Abstract

Project Summary
A limited understanding of clinically relevant signaling pathways has limited the development of therapeutic
agents for human glomerular disease. Our long-term goal is to enhance the pipeline of putative therapeutic
targets available to tackle human glomerular disease by elucidating the details and functional significance of
key signaling pathways that regulate podocyte injury and survival. Our preliminary data have identified YAP,
the key effector of the Hippo signaling pathway, as an important regulator of podocyte survival. YAP
inactivation in podocytes causes FSGS in mice and decreased YAP expression is associated with the
development and progression of human glomerular disease. We have detected increased intracellular calcium
uptake and marked upregulation of calcium-gated potassium channel expression in YAP silenced podocytes.
The overall objective of this application is to define the mechanism by which YAP regulates podocyte survival
and test its role as a potential therapeutic target. Our central hypothesis is that YAP is inactivated in podocytes
by canonical phosphorylation and cytoplasmic sequestration under the influence of the Hippo kinase LATS.
YAP expression and function can also be regulated at the genetic and transcriptional level. Decreased YAP
signaling enhances purinergic receptor-mediated calcium uptake in podocytes and calcium-gated potassium
channel activation contributing to disruption of the actin cytoskeleton. The rationale for the proposed research
is that defining the underlying mechanisms that regulate YAP function will advance understanding of
glomerular disease progression as well as the quest for novel therapeutic targets available for clinical use. Our
hypothesis will be tested by pursuing two specific aims: Aim 1 will explore the functional significance of YAP
phosphorylation and nuclear-cytoplasmic shuttling in podocyte survival. We will determine whether cytoplasmic
YAP expression in podocytes enhances injury susceptibility and enhancing nuclear YAP signaling is protective
in proteinuric kidney disease. We will also develop a novel YAP agonist and test its role in protecting
podocytes from injury. In Aim 2 we will determine the key signaling pathways and cellular structural changes
induced by YAP inactivation. Our innovative approach utilizes state of the art microfabricated 3-D chips,
electrophysiology and atomic force microscopy to quantify the biophysical properties of podocytes during YAP
inhibition and activation under normal and disease conditions. By homology modeling, we will generate novel
small molecule YAP agonists that could be protective in proteinuric kidney disease. These contributions are
significant because they have the potential to not only advance understanding of the pathogenesis of
glomerular disease but could help identify novel therapeutic targets.

## Key facts

- **NIH application ID:** 10433862
- **Project number:** 5R01DK122807-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kirk N Campbell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $526,542
- **Award type:** 5
- **Project period:** 2019-09-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433862

## Citation

> US National Institutes of Health, RePORTER application 10433862, Hippo-YAP in podocyte health and disease (5R01DK122807-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433862. Licensed CC0.

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