# Biological Mechanism of FSGS-1

> **NIH NIH R37** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $413,901

## Abstract

This project continues to build on our-long-term goal of identifying and understanding genes which when
altered cause human kidney disease. Mutations in alpha-actinin-4 (ACTN4) cause a form of kidney disease
characterized by progressive decline in function, proteinuria, and focal segmental glomerulosclerosis
(FSGS). We have made substantial progress during the current award period in understanding the role of
mutation-induced alterations in ACTN4-actin affinity on the biophysical properties of the actin network at in
vitro and cellular levels. We demonstrated that genetic alterations in ACTN4 have profound effects on cell
behavior including contractility, motility, response to stretch, and gene transcription, and ultimately produce
glomerular pathology in the organism. We have generated strong evidence that phosphorylation events can
reversibly modulate the ACTN4-actin affinity. These findings suggest a model where the global effects of
ACTN4 disease-mutations on strain hardening and network brittleness are detrimental, and where ACTN4
phosphorylation allows for similar, but local and spatiotemporally regulated, changes to the actinin-actin
network.
Our working hypothesis is that a normally hidden actin-biding site (ABS1) is required for strain-dependent
network hardening but at the expense of generating a more brittle cytoskeleton. Mutation or phosphorylation
exposes this site. We will further define the role of ACTN4 S159 phosphorylation in regulating the cellular
actin cytoskeleton, cellular adhesion and contractility, and lastly, in regulating in vivo podocyte function. We
will use these studies as a springboard for identifying the signals, kinases and phosphatases regulating
ACTN4 phosphorylation. Finally, we will elucidate the importance of ABS1-mediated strain hardening in cells
and in vivo. This next set of studies extend and expand upon the aims of the original proposal, and will
advance our understanding of not only ACTN4-mutation induced FSGS but also elucidate the importance of
spatiotemporal regulation of the actinin-actin network through phosphorylation events.
Specifically, we will: 1. Define the cellular role and regulation of ACTN4 by serine 159 phosphorylation; 2.
Define the relationship between ACTN4-mediated, biophysical behavior of cells, alterations to the local
microenvironment, and its regulation by phosphorylation; 3. Define the role of regulation of the ABD of
ACTN4 by phosphorylation and mutation in the function of the kidney in vivo using new CRISPR-derived
animal models we have developed; 4. Extend our understanding of the effects of ACTN4 alterations in
regulating gene expression.

## Key facts

- **NIH application ID:** 9928915
- **Project number:** 5R37DK059588-21
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** MARTIN R. POLLAK
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,901
- **Award type:** 5
- **Project period:** 2016-07-21 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928915

## Citation

> US National Institutes of Health, RePORTER application 9928915, Biological Mechanism of FSGS-1 (5R37DK059588-21). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9928915. Licensed CC0.

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