# Regulating fibrosis and growth through latent TGFbeta binding proteins

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $395,000

## Abstract

PROJECT SUMMARY
Latent TGF binding protein 4 (LTBP4) modifies muscular dystrophy in mice and in humans with Duchenne
Muscular Dystrophy. LTBP4 is an extracellular matrix protein that binds latent TGFβ to form the large latent
complex. With stimulation like injury, LTBPs undergoes a conformational shift and proteolytic cleavage which
releases latent TGFβ, which is the first step in its activation. Activated TGFβ has been implicated in fibrosis in
many solid organs, and is a prominent feature of dystrophic muscle and injured muscle. Excessive TGFβ is
also known to inhibit muscle regeneration. In Duchenne Muscular Dystrophy, the protective LTBP4 variants
that predict prolonged ambulation cause reduced TGFβ signaling. Similarly, in mice the protective Ltbp4 allele
is linked to reduced TGFβ signaling. LTBP4 binds all three primary TGFβ forms. Overexpression of the
protective LTBP4 form in mouse muscle reduces fibrosis and also leads to increased muscle mass in the
context of muscular dystrophy. LTBP4 not only binds TGFβ but LTBP4 also binds myostatin. Domain
mapping of LTBP4 binding sites demonstrated that TGFβ and myostatin binding is mediated by distinct regions
of LTBP4. LTBP4 therefore regulates multiple cytokines by sequestering these molecules in the matrix,
rendering them inactive. A mechanism to reduce TGFβ AND myostatin is an attractive target for treating
muscular dystrophy since such an approach would reduce muscle fibrosis and promote muscle growth. This
proposal outlines experiments designed to better define the mechanism by which LTBP4 acts. The first aim is
designed to evaluate the relative contribution of TGFβ and myostatin binding to LTBP4's effect. The second
aim will investigate how manipulating LTBP4 affects fibrosis and muscle recovery after injury and in muscular
dystrophy. The third aim will assess the importance of LTBP4's hinge region since this region mediates its
effect as a modifier in muscular dystrophy.

## Key facts

- **NIH application ID:** 9857651
- **Project number:** 5R01HL140938-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elizabeth M McNally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857651

## Citation

> US National Institutes of Health, RePORTER application 9857651, Regulating fibrosis and growth through latent TGFbeta binding proteins (5R01HL140938-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857651. Licensed CC0.

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