# Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease

> **NIH NIH UH3** · DUKE UNIVERSITY · 2020 · $1,122,799

## Abstract

ABSTRACT
The initiation and progression of atherosclerosis is influenced by systemic inflammation and individuals
suffering from autoimmune diseases, such as rheumatoid arthritis, have increased risk of developing
cardiovascular diseases. Likewise, chronic and systemic inflammation in rheumatoid arthritis induces muscle
wasting and loss of function. Therapies that reduce inflammation effectively treat rheumatoid arthritis and
have the potential to reduce the severity of cardiovascular disease. To overcome limitations of animal
models replicating some key disease phenotypes, but not the underlying mechanisms, we established
functional human microphysiological systems (hMPS) for healthy human skeletal and cardiac muscle and
endothelialized tissue-engineered blood vessels (eTBEVs) using primary and iPS-derived cells and assessed
the response to drugs and pro-inflammatory cytokines. These models replicate the structure and key functions
of the native tissue and maintain their structure and function for at least 4 weeks. These in vitro tissue
systems accurately model the response to drugs. Our goal in this project is to develop clinically relevant
hMPS disease models to examine rheumatoid arthritis (RA) risk for muscle dysfunction and atherosclerosis
and the role of exercise in attenuating disease-associated inflammation. To meet this goal, we will expand our
preliminary results to develop and validate an early atherosclerosis model that uses flow conditions promoting
endothelial dysfunction, macrophage accumulation, foam cell formation, and altered vasoactivity. We will
reproduce the RA phenotype in skeletal and cardiac muscle through addition of macrophages and cytokines
present in RA, and demonstrate that simulated exercise conditions on muscle produce myokines that reduce
inflammation in this RA model. Then, we will develop an integrated perfusion system for eTEBVs, skeletal
and cardiac muscle and show that the RA model can increase macrophage accumulation in eTEBVs and
cardiac bundles, and assess the response to exercise and drugs to treat atherosclerosis and inflammation.
We will use CRISPR gene editing technology to generate mutations to proprotein convertase subtilisin/kexin
type 9 (PCSK9) and genes that affect IL-6 shedding to assess their impact on endothelial dysfunction and
foam cell formation in eTEBVs, and inflammation in skeletal and cardiac muscle bundles. We will profile
cytokines and metabolites in the models with and without RA, and demonstrate that disease progression and
biomarkers are reduced in the presence of common anti-inflammatory therapeutic interventions for
atherosclerosis, and assess the effect of exercise. Likewise, in the RA muscle model, we will examine whether
gene variants produce alterations in cytokine profiles impacting muscle function and response to exercise;
these may point toward new disease-associated biomarkers and therapeutic targets. Results of this project
will provide a general framework for in vitro mo...

## Key facts

- **NIH application ID:** 10009489
- **Project number:** 5UH3TR002142-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** George A Truskey
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,122,799
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009489

## Citation

> US National Institutes of Health, RePORTER application 10009489, Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease (5UH3TR002142-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10009489. Licensed CC0.

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