# KIBRA-induced biomechanical changes and therapeutic targeting in podocytes

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $71,555

## Abstract

Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte
loss remain poorly understood, and cell-specific therapy is lacking. Our long-term goal is to elucidate critical
signaling pathways that disrupt podocyte cytoarchitecture in order to identify targets for therapeutic intervention
for glomerular diseases. Our work has identified KIBRA (encoded by WWC1) as a key regulator of glomerular
disease progression, podocyte cytostructure, and podocyte injury via downstream LATS kinase activation and
YAP inhibition in the canonical Hippo signaling pathway. However, little is known about the regulation of
WWC1/KIBRA expression, and therapeutic implications for KIBRA upregulation in FSGS and diabetic
nephropathy remain unclear. Additionally, our preliminary data support non-canonical direct KIBRA downstream
regulation of transcription factors TEAD 1-4. The overall objectives of this application are to define the regulators
of WWC1/KIBRA expression and function in podocytes, test non-canonical KIBRA-TEAD signaling, and to target
LATS and TEAD as novel therapeutic strategies for KIBRA-mediated and diabetic podocyte injury. Based on our
preliminary RNA-seq analysis, our central hypothesis is that WWC1/KIBRA function in podocytes is repressed
by the micro-RNA 200 family and regulated by transcription factors such as SOX4. In addition to canonical KIBRA
regulation of LATS/YAP, KIBRA non-canonically directly suppresses TEAD 1-4 expression. Together, these
downstream signaling events disrupt podocyte structural integrity and podocyte-glomerular basement membrane
(GBM) adhesion, thereby promoting glomerular disease progression. The rationale for the proposed research is
that testing novel regulators of KIBRA, non-canonical KIBRA signaling, and both novel canonical and non-
canonical therapeutic approaches will significantly increase understanding of the mechanisms underlying
glomerular disease progression and advance the quest for new selective treatments. Our hypothesis will be
tested by pursuing three specific aims: Aim 1 will test novel micro-RNA and transcriptional regulation of
WWC1/KIBRA expression and function and will define the biomechanical sequelae of KIBRA-mediated podocyte
structural disruption. Aim 2 will test downstream KIBRA non-canonical regulation of TEAD 1-4 and the effects of
LATS kinase depletion and inhibition in vitro and in vivo. Aim 3 will test the therapeutic efficacy of pharmacologic
TEAD agonists and LATS inhibitors individually and combined as multi-targeted therapy for KIBRA-mediated
and diabetic disease models in vitro and in vivo. The work proposed here is expected to define disease relevant
regulators of podocyte KIBRA expression and elucidate novel targets and treatment strategies for glomerular
diseases. In this diversity supplement, we will specifically focus on investigation of the therapeutic effects of
LATS inhibitors in KIBRA-mediated and hyperglycemia-induced podocyte in...

## Key facts

- **NIH application ID:** 11088420
- **Project number:** 3R01DK135999-01A1S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kristin Meliambro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $71,555
- **Award type:** 3
- **Project period:** 2024-08-19 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11088420

## Citation

> US National Institutes of Health, RePORTER application 11088420, KIBRA-induced biomechanical changes and therapeutic targeting in podocytes (3R01DK135999-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11088420. Licensed CC0.

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