# Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2020 · $403,786

## Abstract

PROJECT SUMMARY
Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting males and
females, children and adults. In the majority of clinical FSHD cases, muscle weakness is not noticeable
until the second or third decade of life followed by a progressive pathology impacting many facets of
everyday life, ranging from being unable to comb one's own hair or walk the dog to including having to
change or abandon careers, loss of independence and, in ~20% of FSHD patients, becoming
wheelchair bound and/or require aid in breathing. Currently there are no treatments to slow
down, stop, or reverse disease progression. Recent advances have identified the aberrant expression
of the DUX4 transcription factor as the primary initiator of the FSHD pathogenic cascade of events. In
vitro studies have identified numerous DUX4-mediated events that have adverse effects on cell
viability and function and could conceivably lead to muscle disease if they were to happen in the
context of an actual person. However, due to the complexities of FSHD and the lack of any valid
animal model for FSHD, which, if any, of these pathways actually has pathogenic relevance. We have
successfully generated and validated a phenotypic FSHD-like mouse model based on DUX4 expression.
This allows, for the first time, the interrogation of downstream effects of DUX4 expression as to
potential roles in pathophysiology and validation as therapeutic targets. We will initially focus on the
innate immune response. The major gene expression signature from FSHD muscle biopsies indicates
the immune response is highly activated in FSHD muscle . Many other muscular
dystrophies have immune system components and there are many available ameliorative
treatments for these muscular dystrophies that target the inflammatory response. Identifying the
inflammatory response as a key mechanism in developing FSHD pathology would be a significant
advance and open many new avenues for therapeutic intervention. In addition, the design of the model
allows us to initiate DUX4 expression in adult animals . Therefore, we will use our FSHD-like
mouse model to identify potential biomarkers of disease progression and compare with what
has been found in human biospecimens. Importantly, in our mice we will be able to distinguish
early, initiating events from those due to long-term cumulative effects and this may help determine
which biomarkers correlate more directly with DUX4 expression and are the best to follow as the field
moves to clinical trials.

## Key facts

- **NIH application ID:** 9966886
- **Project number:** 5R01AR070432-06
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Peter L Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,786
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966886

## Citation

> US National Institutes of Health, RePORTER application 9966886, Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy (5R01AR070432-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9966886. Licensed CC0.

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