# Revealing New Therapeutic Opportunities for Kidney Glomerular Diseases by Elucidating the Mechanobiological Functions of Novel Cytoskeletal Structures in Podocytes

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $820,119

## Abstract

Project Summary
Chronic kidney diseases, of which glomerular diseases form the most significant component, are quite
common and estimated to affect from 5 to 11% of the population. Specific treatment options for various
forms of chronic kidney disease in general are extremely limited, in part due to the poor understanding of
the pathogenesis of glomerular diseases. What has been apparent since the advent of electron
microscopic visualization of the glomerular filtration barrier is that loss of typical podocyte foot process
architecture, termed podocyte foot process effacement, is a hallmark of proteinuric glomerular diseases.
The overall goal of this research is to better understand the mechanisms that ensure podocyte
homeostasis, the maintenance of normal podocyte architecture and adhesion to the glomerular
basement membrane, and the pathogenic mechanisms that promote podocyte foot process effacement
and the subsequent detachment. By better understanding these mechanisms, targeted therapies to
intervene in these pathways can be designed to improve the outcomes of patients either already living
with or at risk of glomerular disease. Proof of concept therapeutic approaches are proposed in this
project.
The overall focus of this application involves several mechanistic aspects of podocyte cytoskeletal
dynamics in relation to slit diaphragm stability, foot process shape, and adhesion to the underlying GBM
through integrins. Our hypothesis is that podocyte foot process adhesion dynamics can be
controlled by modulating tensional homeostasis in cytoskeletal networks of both contractile and
non-contractile actin cables that bind integrins and slit diaphragms. The Specific Aims are focused
on the functions of synaptopodin (Aim 1), CD2-associated protein (CD2AP; Aim 2), and integrin-based
podocyte adhesion in health and disease states (Aim 3). We will investigate how these three aspects of
podocyte biology cooperate and interact with each other to ensure podocyte homeostasis under the
constant stress of filtration. We will use several novel, innovative approaches to carry out the Aims and
will use our mouse models of nephrotic syndrome and Alport syndrome as highly relevant human
disease models. The results of the proposed experiments, which also have biochemical,
mechanobiological, state of the art imaging, and primary podocyte cell culture components, will lead to
an improved understanding of diverse aspects of podocyte biology and reveal clear pathways towards
the development of new therapies for patients.

## Key facts

- **NIH application ID:** 11000153
- **Project number:** 1R01DK141178-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Guy M Genin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $820,119
- **Award type:** 1
- **Project period:** 2024-08-08 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11000153

## Citation

> US National Institutes of Health, RePORTER application 11000153, Revealing New Therapeutic Opportunities for Kidney Glomerular Diseases by Elucidating the Mechanobiological Functions of Novel Cytoskeletal Structures in Podocytes (1R01DK141178-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11000153. Licensed CC0.

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