# Contribution of Macropinocytosis in fibroblast activation and systemic sclerosis

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2022 · $211,200

## Abstract

PROJECT SUMMARY/ABSTRACT
This R21 proposal describes a two-year research plan that will facilitate research program dedicated to
determining the role of macropinocytosis in systemic sclerosis (SSc, scleroderma) and SSc-associated interstitial
lung disease (ILD). SSc is an autoimmune disorder, which is manifested by skin fibrosis, vasculopathy and the
fibrosis of internal organs. The prevalence of SSc is estimated to range from 50 to 300 per million across the
world, with one of the highest prevalence rates observed in the United States at 240 per million. Because of its
clinical heterogeneity, SSc is a challenging disease to manage which results in the highest disease mortality
among the rheumatologic diseases. ILD is the most common lung complication of SSc and is associated with
increased mortality. ILD occurs in up to 80% of patients with SSc, with 25–30% developing a severe progressive
form of SSc-ILD leading to eventual respiratory failure and death. Little is known about the molecular
mechanisms involved in the pathogenesis of SSc and SSc-ILD. This project will focus on elucidating the key
roles of macropinocytosis in skin and lung fibrogenesis, as well as its therapeutic targeting. Macropinocytosis is
an actin-dependent but clathrin-independent endocytic process that mediates the nonselective internalization of
extracellular contents, such as proteins, cell debris, or viruses. Macropinocytosis has been shown to be involved
in cell survival, migration and invasion by providing nutrients (e.g., free amino acids and polypeptides) from
extracellular environment. However, its role in scleroderma and organ fibrogenesis is unknown. Our preliminary
findings suggest that inhibition of macropinocytosis attenuates dermal myofibroblast differentiation and
pulmonary fibrosis in mice. Furthermore, we found that vacuolar protein sorting 34 (Vps34), a sole member of
class III phosphoinositide-3-kinase (PI3K), is involved in macropinocytosis and fibroblast activation. Based on
published and our preliminary findings, we hypothesize that increased macropinocytosis promotes the
development of dermal and lung fibrosis in SSc. Thus, its inhibition exerts anti-fibrotic effects in the
animal model of skin fibrosis by reducing profibrotic responses in activated fibroblasts. We also
hypothesize that Vps34 is essential for macropinocytosis, which in turn confers to fibroblast activation.
We will test our hypotheses by addressing the following Specific Aims: Specific Aim #1: To demonstrate that
macropinocytosis inhibition attenuates dermal and lung fibrosis in mice by inhibiting fibroblast to myofibroblast
differentiation, ECM production, and migration. Specific Aim #2: To demonstrate that Vps34 is a key protein in
macropinosome formation and contributes to profibrotic responses of dermal and lung fibroblasts.

## Key facts

- **NIH application ID:** 10353766
- **Project number:** 1R21AR080332-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Konstantin Tsoyi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $211,200
- **Award type:** 1
- **Project period:** 2022-02-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353766

## Citation

> US National Institutes of Health, RePORTER application 10353766, Contribution of Macropinocytosis in fibroblast activation and systemic sclerosis (1R21AR080332-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10353766. Licensed CC0.

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