# Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy

> **NIH NIH R15** · ILLINOIS STATE UNIVERSITY · 2022 · $375,393

## Abstract

Project Summary/Abstract:
 Duchenne Muscular dystrophy (Dmd) is a lethal degenerative disease affecting 1 in 5,000 males. Dmd
is caused by mutations in the gene encoding dystrophin, a highly conserved protein linking muscle cell
membranes with the extracellular matrix and the contractile machinery within them. Dystrophin has
structural and signaling functions. Loss of dystrophin is linked to muscular and neural degeneration. While
traditional analyses of mice, worms and other animals modeling Dmd genetically, through loss-of-function
mutations in the dystrophin gene, resulted in great advances, these systems have only produced relatively
mild muscular and behavioral phenotypes. To date there is no cure for Dmd.
 To model the acute muscle degeneration observed in Dmd patients in a model system amenable to
genetics we developed a fast and inexpensive nematode assay. Our assay elicits strong behavioral and
cellular phenotypes in dystrophic (dys-1) nematodes to a degree not previously attained in other systems.
During our previous award cycle, we improved our assay to allow automatization and medium to high
throughput screening of candidate treatments. We went on to characterize many dystrophic phenotypes
and found that they first arise during embryogenesis. We also identified the first neurological impairments
in dystrophic worms, where the sensory function of ASH neurons is impaired. A suppressor mutant, and
an RNA-interference screen both pointed to calmodulin as a therapeutic target. The first specific aim of this
project is to characterize the onset of dystrophic phenotypes during myogenesis, and to separate the
contribution of dystrophin’s signaling and structural roles to these deficits. This will identify the
mechanism by which muscles become impaired during development. The second aim is to characterize the
role dystrophin plays in the structure and function of the ASH neurons. These well-studied neurons will
provide an amenable springboard to study the neuropathophysiology of Dmd. In the third aim, we will use
our assay to identify downstream effectors of calmodulin responsible for the prevention of dystrophic
phenotypes observed following reduction of calmodulin function in dys-1 animals. Identifying these
effectors will be key to finding safe treatment avenues, sparing additional processes mediated by
calmodulin. To validate our findings and bridge the gap to humans, we will use humanized dystrophic
nematodes and human myogenic cell lines. Completion of these aims will provide key insights into Dmd
pathophysiology and identify new molecular targets and pathways that can be used to treat this disease.

## Key facts

- **NIH application ID:** 10439290
- **Project number:** 2R15AR068583-02
- **Recipient organization:** ILLINOIS STATE UNIVERSITY
- **Principal Investigator:** Andres Gabriel Vidal Gadea
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,393
- **Award type:** 2
- **Project period:** 2016-06-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439290

## Citation

> US National Institutes of Health, RePORTER application 10439290, Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy (2R15AR068583-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10439290. Licensed CC0.

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