# Dynamin, actin and microtubules: cytoskeletal crosstalk in podocytes

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $376,020

## Abstract

Project Summary/Abstract
The global epidemic of chronic kidney disease is progressing at an alarming rate. In the United States alone,
glomerular kidney diseases affect some 20 million people, and this number has roughly doubled in the last two
decades. Kidney-related diseases are rapidly eluding current available treatment options and resources.
Podocytes are unique cells within the kidney glomerulus, which have a complex organization consisting of a
cell body, microtubule-driven membrane extensions (primary processes), and actin-cytoskeleton driven
membrane extensions (foot processes). Since the podocyte cytoskeleton is composed of three distinct
elements - actin filaments, microtubules, and intermediate filaments - their cytoskeleton must be coordinately
regulated for podocytes to fulfill their complex cellular function. Coordination between cytoskeletal elements is
achieved through signaling pathways, which involve common regulators such as Rho GTPases as well as the
large GTPase dynamin. We have shown that dynamin directly regulates the actin cytoskeleton in podocytes.
Our novel findings suggest that dynamin also regulates microtubules – specifically that dynamin forms helices
around microtubules. Dynamin helices exhibit very high rates of GTP hydrolysis, which in turn inhibit
microtubule polymerization by lowering the local concentration of GTP. A high GTP concentration is required
for efficient tubulin oligomerization since tubulin uses GTP binding to initiate its polymerization into
microtubules. Additionally, high rate of GTP hydrolysis by dynamin helices also constricts microtubules to a
small radii, thus destabilizing microtubules and initiating microtubule catastrophe. Therefore, these two
GTPases, dynamin and tubulin, are regulated by the availability of GTP in their vicinity and dynamin's ability to
oligomerize into helices around microtubules. The ability of dynamin to directly affect dynamics of microtubules
and actin suggests that dynamin might be one of the proteins in podocytes that these two cytoskeletal proteins
use to communicate with each other. In Specific Aim 1 we use real time single-molecule imaging to decipher
mechanistic details of dynamin-microtubule and dynamin-actin interactions. In Specific Aim 2 we use a panel of
diverse dynamin mutants, podocyte cell culture, biochemistry using purified proteins, and electron microscopy
to investigate the role that dynamin plays in regulating microtubules in podocytes, and how microtubules affect
the formation of focal adhesions and stress fibers. In Specific Aim 3 we test our hypothesis in animals by using
our novel dynamin-specific mouse model, and a mouse model of HIV-associated nephropathy (HIVAN). We
test whether a dynamin mutant that has the propensity to oligomerize and is expected to promote microtubule
depolymerization can counteract podocyte injury by using microtubule drugs that either promote or inhibit
microtubule polymerization. Given the essential role of microtub...

## Key facts

- **NIH application ID:** 9918327
- **Project number:** 5R01DK093773-08
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Sanja Sever
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,020
- **Award type:** 5
- **Project period:** 2011-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918327

## Citation

> US National Institutes of Health, RePORTER application 9918327, Dynamin, actin and microtubules: cytoskeletal crosstalk in podocytes (5R01DK093773-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9918327. Licensed CC0.

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