# Developing New Diagnostic and Timed, TAK1 Specific Treatment Strategies for Trauma Induced Heterotopic Ossification

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $301,380

## Abstract

PROJECT SUMMARY
 Pathology stemming from excess ectopic bone formation, or trauma-induced heterotopic ossification (HO),
presents a substantial barrier to recovery in 20% of patients with hip replacements, musculoskeletal trauma,
spinal cord injury, amputations and burn injuries. Patients with HO experience chronic pain, restricted joint
function, and open wounds; they often undergo surgical procedures to excise the offending bone, but these
procedures fail to reverse the joint contractures and restricted range of motion and can lead to recurrence.
With these limitations in our understanding of HO and our inability to prevent its development, we set out to
clarify the cells responsible (mesenchymal cells and macrophages) and primary signaling pathway involved.
 Whole transcriptome sequencing and immunofluorescent imaging of the early HO site have demonstrated a
marked increase in Transforming Growth Factor-beta activating kinase 1 (TAK1) signaling in the mesenchymal
cells. However, the stage of mesenchymal cell differentiation in which TAK1 is necessary and what cells
stimulate mesenchymal cell TAK1 remains unknown. Preliminary data demonstrate that gene and therapeutic
knockdown of TAK1 mitigates early mesenchymal condensation and differentiation responsible for HO.
Importantly, we have also demonstrated the central role of macrophages and their activation of TAK1 in
mesenchymal cells. We plan to validate a novel cell specific drug delivery system to block secretion of a
primary ligand (Transforming Growth Factor 1β) from a primary cell (macrophage) responsible for HO.
The following aims are designed to test our hypothesis that the overall treatment paradigm of HO will be
improved with early detection using high frequency spectral ultrasound and timed, pathway and cell specific
inhibition of TAK1 signaling.
· Aim 1: To define the pathway of TAK1 signaling in mesenchymal cells after trauma and to validate
 novel TAK1 pathway inhibitors to prevent heterotopic ossification. This aim will demonstrate that
 TAK1 signaling is upregulated during mesenchymal condensation and that genetic knockout of TAK1
 specifically in mesenchymal cells or early TAK1 pharmacologic inhibition with small molecule NG-25 will
 mitigate HO through an Arkadia/SMAD7 mediated process. This aim will utilize novel imaging to allow
 detection of early pre-HO changes and validate an early timed treatment strategy to prevent HO.
· Aim 2: To define the role of macrophage-specific TGFβ1 production on HO and to validate novel
microparticles that silence Tgfb1 specifically in macrophages. This aim will demonstrate that injury
site macrophages and their production of TGFβ1 is critical for ectopic mesenchymal cell TAK1 signaling,
chondrogenesis and HO. This aim will also optimize microparticles for macrophage-specific uptake and
drug delivery to administer Tgfb1 siRNA and prevent HO.

## Key facts

- **NIH application ID:** 10216084
- **Project number:** 7R01GM123069-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Benjamin Levi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,380
- **Award type:** 7
- **Project period:** 2017-08-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216084

## Citation

> US National Institutes of Health, RePORTER application 10216084, Developing New Diagnostic and Timed, TAK1 Specific Treatment Strategies for Trauma Induced Heterotopic Ossification (7R01GM123069-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10216084. Licensed CC0.

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