# A MIR-486/DOCK3 SIGNALING AXIS MODULATES DYSTROPHIN-DEFICIENT PATHOLOGY

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $328,750

## Abstract

PROJECT SUMMARY
Duchenne muscular dystrophy (DMD) is an X-linked disorder that affects 1:5000 live male births in the US each
year. DMD is caused by loss-of-function mutations in the DYSTROPHIN (DMD) gene that results in severe
muscle wasting, loss of ambulation by age 12, cardiac arrhythmia, and death in early adulthood due to respiratory
failure. While there are several novel strategies (such as exon-skipping compounds to create partially-functional
Dystrophin protein) in clinical trials, none of them deal with the secondary signaling pathways and subsequent
muscle pathogenesis that occurs in DMD. There is growing evidence that genetic modifiers of DMD have a
significant impact on the outcomes and severity of DMD-related pathologies in patients. These DMD genetic
modifiers have the potential to serve as novel therapeutic entry points for the treatment of diseases. Previously
my laboratory identified miR-486 as a muscle-enriched microRNA that is decreased in expression in DMD patient
skeletal muscle biopsies.
In this proposal, we will test the hypothesis that miR-486 and its target (DOCK3) play a significant role in
the regulation of skeletal muscle. We have strong data that demonstrates that miR-486 expression levels
decrease and an mRNA target (DOCK3) increases corresponding with the degree of dystrophic pathology. In
Aim 1, we will characterize the functional role of miR-486 on skeletal and heart muscles via characterizing
muscle performance and cardiac remodeling in miR-486 knockout (KO) mice on normal and mdx5cv backgrounds.
Aim 2 focuses on identifying the consequences of manipulating miR-486 and Dock3 expression on key
downstream signaling pathways including PTEN/AKT and Rac1/RhoA using a novel Dock3 conditional muscle
knockout mouse. Additionally, we will identify novel miR-486 target genes using Ago2-sequencing (CLIP-seq)
strategy to identify in vivo skeletal muscle targets of miR-486. Lastly, Aim 3 focuses on using transient miR-486
overexpression strategies (Adeno-associated viral vectors and engineered exosomes) delivered intramuscularly
and systemically to improve dystrophic symptoms at key developmental time points in mdx5cv mice. Our
combinatorial use of DMD patient muscle cell lines, miR-486 KO and Dock3 conditional muscle KO mice,
and experience evaluating genetic and drug compounds in mouse models of human diseases will allow
us to rigorously evaluate the use of a microRNA (miR-486) overexpression as a novel therapy for the
treatment of DMD.

## Key facts

- **NIH application ID:** 10171875
- **Project number:** 5R01HD095897-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** MATTHEW Scott ALEXANDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $328,750
- **Award type:** 5
- **Project period:** 2018-08-17 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171875

## Citation

> US National Institutes of Health, RePORTER application 10171875, A MIR-486/DOCK3 SIGNALING AXIS MODULATES DYSTROPHIN-DEFICIENT PATHOLOGY (5R01HD095897-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10171875. Licensed CC0.

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