# Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndrome

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $177,021

## Abstract

Project Summary:
Myhre syndrome is a rare disorder caused by de novo mutations in the SMAD4 gene
(SMAD4 missense mutation at the codon for Ile500). As a connective tissue disorder,
core symptom of Myhre syndrome is life-threatening progressive fibrosis in multiple
organs (thickening and scarring of connective tissue) affecting the structure or function
of the heart, the respiratory system, the gastrointestinal system, and the skin. However,
like many other rare diseases, Myhre syndrome remains significantly understudied with
respect to etiologic mechanisms of how pathogenic SMAD4 mutation leads to the
disorder. Particularly, there is no available treatment for this disease to date.
The SMAD signaling network controls a vast array of biological processes. We have
previously reported that SMAD signaling modulates stem cell function, lineage
differentiation and regeneration in epithelial organs (Mou et al., Cell Stem Cell, 2016). In
this proposal, we will test a hypothesis that the accumulative cell senescence caused by
gain-of-function of SMAD4 mutation is one of etiologic mechanisms underlying the organ
dysfunction and fibrosis of Myhre syndrome. To test this hypothesis, we have recently
developed a conditional SMAD4-I499V knock-in mouse as a physiologically relevant
model of Myhre syndrome. In specific aim 1, we will examine the progression of
phenotypical, physiological, and functional changes in various tissues throughout the
entire mouse lifespan. In addition, we will quantify age-dependent senescence-related
pathways and signatures and examine if accumulative cellular senescence is tightly
associated with progressive fibrosis. In specific aim 2, we will use skin fibrosis as model
and propose a pilot study to test if pharmacological targeting of cell senescence is able
to alleviate skin fibrogenesis. This study will provide the scientific evidences to establish
the persistent and accumulative cellular senescence as a pathogenic mechanism of the
fibrotic manifestations in Myhre syndrome. Thus, the early attenuation of senescence-
related pathways or/and elimination of senescent cells can be a promising therapeutic
approach to prevent tissue fibrosis in Myhre syndrome patients.

## Key facts

- **NIH application ID:** 10425541
- **Project number:** 1R21AR080778-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MARK E LINDSAY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $177,021
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425541

## Citation

> US National Institutes of Health, RePORTER application 10425541, Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndrome (1R21AR080778-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425541. Licensed CC0.

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