# Innate Immune Activation in Autoimmune Myopathy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $393,868

## Abstract

PROJECT SUMMARY/ABSTRACT
The idiopathic inflammatory myopathies (IIMs) represent a group of systemic autoimmune disorders in which
muscle and extra-muscular organs are targeted for immune-mediated destruction. We have previously
established a model of histidyl-tRNA synthetase (HRS)-induced myositis that involves MyD88-dependent
innate immune signaling pathways featuring Toll-like receptors 2 and 4 (TLR2, TLR4). Given the prominent
role of these TLRs in our model of HRS-induced myositis, we hypothesize that heightened activation of the
downstream transcription regulator NF-κB is ultimately responsible for various inflammatory cascades as well
as non-immune pathways promoting muscle dysfunction in this system—effectively linking HRS-induced
myositis/IIM with other disorders (including muscular dystrophy as well as sepsis- and trauma/ischemia-
induced myopathies) in which NF-κB dysregulation contributes to muscle inflammation, muscle degeneration,
and impaired regenerative potential. Through a series of in vitro culture systems and in vivo immunization
strategies involving knockout mice lacking critical components of MyD88-dependent signaling pathways, we
will systematically examine the impact of HRS-induced TLR signaling and NF-κB activation on T cell migration,
T cell activation, and muscle weakness. While Specific Aim 1 will focus on HRS-induced changes in T cell
function and TLR-mediated activation of vascular endothelium (leading to lymphocytic infiltration of target
organs), Specific Aim 2 will define direct and indirect pathways of HRS-induced NF-κB activation in muscle
tissue through in vitro myoblast stimulation assays as well as additional immunization studies focusing on
correlations between muscle inflammation, NF-κB activation, and in vivo/ex vivo parameters of muscle
weakness. Complementary in vivo assessment tools including MRI and the use of NF-κB-luciferase transgenic
mice will further define the relationship between HRS-mediated NF-κB activation and muscle dysfunction,
providing the foundation for experimental trials of comparative NF-κB inhibition in Specific Aim 3. Collectively,
these studies will elucidate the contribution of innate immunity to the pathogenesis of IIM, supplementing more
traditional paradigms of antigen-specific, adaptive immune recognition and identifying therapeutic targets that
are potentially relevant to a range of human inflammatory muscle diseases.

## Key facts

- **NIH application ID:** 9926715
- **Project number:** 5R01AR071369-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** DANA P ASCHERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,868
- **Award type:** 5
- **Project period:** 2017-04-10 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926715

## Citation

> US National Institutes of Health, RePORTER application 9926715, Innate Immune Activation in Autoimmune Myopathy (5R01AR071369-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926715. Licensed CC0.

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