NIH grant: Defining the role of SLC9A1 in fibroblast pathobiology during Systemic Sclerosis and Systemic Sclerosis-associated Interstitial Lung Disease (1R01AR086894-01A1)

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NIH grant 1R01AR086894-01A1: Defining the role of SLC9A1 in fibroblast pathobiology during Systemic Sclerosis and Systemic Sclerosis-associated Interstitial Lung Disease
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: Konstantin  Tsoyi. Award: $608966.
Start: 2026-08-26T00:00:00.
PROJECT SUMMARY/ABSTRACT
This R01 proposal describes a five-year research plan that will facilitate a 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 dermal fibrosis, the fibrosis
of internal organs, including lungs, and vasculopathy. The molecular mechanisms involved in the pathogenesis
of SSc are not fully understood. This project will focus on elucidating the key roles of Na+/H+ exchanger isoform
1 (NHE1/SLC9A1) in skin and lung fibrogenesis, as well as its therapeutic targeting. Macropinocytosis, one of
the major cellular events driven by SLC9A1 activation, is the cellular process of internalization of extracellular
contents, such as proteins and free amino acids. Macropinocytosis has been shown to be involved in cell survival,
migration, and invasion by providing nutrients (e.g., free amino acids and polypeptides) from the extracellular
environment. However, its role in SSc or SSc-ILD is also currently unknown. We found that Na+/H+ exchanger
isoform 1 (NHE1/SLC9A1), plays a key role in macropinocytosis regulation and fibroblast activation. Based on
published and our preliminary findings, dysregulation of SLC9A1 promotes dermal and lung fibrosis in
experimental models of SSc. We will test our hypothesis by addressing the following Specific Aims: Specific
Aim #1: To determine the importance of SLC9A1 in SSc and SSc-ILD experimental models. Specific Aim #2: To
demonstrate that SLC9A1 and macropinocytosis inhibition exert anti-fibrotic effects in fibroblasts isolated from
SSc and SSc-ILD subjects. Specific Aim #3: To determine the molecular mechanisms by which SLC9A1 gets
activated and regulates profibrotic responses in fibroblasts.

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