# Novel probes of BMP and TGF-beta signaling and function

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $266,477

## Abstract

PROJECT SUMMARY/ABSTRACT
Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft
tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms
responsible for HO remain incompletely understood; however, the association with genetic gain-of-
function syndromes affecting receptors and ligands of the bone morphogenetic protein (BMP) and
activin signaling pathways has generated important insights and translatable strategies. We have
previously identified activin A as the dominant ligand responsible for the congenital HO syndrome
fibrodysplasia ossificans progressiva (FOP), being transduced via mutant ACVR1 encoding ALK2. In
subsequent work using a ligand trap, we and collaborators found that ligands of the BMP type I
receptor ALK3 account for a major portion of non-genetic forms of HO, frequently complicating joint
replacement surgeries, burn injuries, blast trauma, or inflammatory arthropathies. In the parent grant
for this supplement we describe several pharmacologic and genetic strategies for narrowing the
identify of ligands and receptors responsible for non-genetic forms of HO, using genetically modified
human derived tissue cultures and genetically modified mouse reagents and tissues. Here we
propose to generate a panel of novel reagents that can selectively target signaling via specific type I
and type II receptors in this pathway in non-transfected or non-engineered tissues, and thus permit
complementary studies in unmodified human and rodent tissues without artifacts due to genetic
modification or off-target effects confounding interpretation. Moreover, these antibody-based reagents
would have pharmacokinetics suitable for in vivo validation studies and could be rapidly translated
into therapies for tissue regeneration or orthopedic applications. Importantly. these studies will
provide a robust set of tools that can be used to further elucidate the molecular blueprint for
development, wound healing, as well as HO involving skeletal muscle and tendon niches, and create
a broad platform for scientific discovery and translational work in musculoskeletal disease.

## Key facts

- **NIH application ID:** 10051129
- **Project number:** 3R01AR057374-07S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** PAUL B YU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $266,477
- **Award type:** 3
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051129

## Citation

> US National Institutes of Health, RePORTER application 10051129, Novel probes of BMP and TGF-beta signaling and function (3R01AR057374-07S1). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10051129. Licensed CC0.

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