# Remediating fibrosis for salivary gland regeneration

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT ALBANY · 2024 · $703,935

## Abstract

ABSTRACT
Although extracellular matrix (ECM) remodeling is required for organ development and is a natural response in tissue
repair, excessive ECM deposition in response to continual stress, injury, or aging is known as fibrosis, which impairs organ
function and the potential for regenerative responses. Fibrosis is a significant cause of morbidity and mortality and
contributes to up to 45% of all deaths in the US. 1-3 Fibrosis of the salivary gland occurs following radiation therapy for
head and neck cancers and in patients with Sjögren’s Disease; however, the mechanisms driving reversibility of salivary
gland fibrosis are not understood and are critical to understand for improved therapeutic development. While fibroblasts
and TGFβ signaling are known to be primary drivers of fibrosis, the inability to target cell-specific effects of TGFβ limits
the usefulness of TGFβ therapeutics due to its pleiotropic effects on immune function. In prior work, we used single-cell
RNA sequencing to identify a Pdgfra+, Pdgfrβ+ co-positive subpopulation as the primary fibrogenic cell type that
overproduces extracellular matrix in response to reversible salivary gland injury. As reduction or reversal of fibrosis could
restore function, the objectives of this proposal are to define the contribution of TGFβ modulation of PDGFRα+ stromal
fibroblasts to matrisome composition and organization that drives reversible and irreversible salivary gland fibrosis and to
test scaffold-mediated transplantation of mesenchymal stromal cells for improved ability to remediate a fibrotic response.
We will address these outstanding questions in the field to better inform future therapeutic approaches to remediate or
reverse fibrosis: 1) How does the TGFβ-driven matrisome change in reversible vs irreversible fibrosis? 2) Can cell-specific
manipulation of TGFβ signaling in fibroblasts control fibrosis? 3) Can scaffold mediated delivery of mesenchymal stromal
cells and their exosomes remediate fibrosis and promote gland regeneration? We will apply transcriptomic, proteomic, and
quantitative histological approaches to reversible and irreversible models of salivary gland fibrosis and organoid models for
human cells to define the cell-type specific responses of fibroblasts to create matrisome changes during fibrosis progression
and recovery. These studies will significantly increase our understanding of the TGFβ-dependent mechanisms that drive
salivary gland fibrosis to inform improved regenerative medicine approaches and establish a foundation for testing novel
therapeutics in organoids and mouse models to modulate TGFβ and other effectors and matrisomal proteins in fibrotic
diseases.

## Key facts

- **NIH application ID:** 10905749
- **Project number:** 2R01DE027953-06
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT ALBANY
- **Principal Investigator:** MELINDA LARSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $703,935
- **Award type:** 2
- **Project period:** 2019-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905749

## Citation

> US National Institutes of Health, RePORTER application 10905749, Remediating fibrosis for salivary gland regeneration (2R01DE027953-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10905749. Licensed CC0.

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