Ribosome Dysfunction in Lung Fibrosis

ABSTRACT Systemic sclerosis (SSc) is a complex autoimmune disease with unknown causes and few effective treatments. SSc predominantly affects women of black ancestry and is a highly debilitating disease. A key feature of SSc is fibrotic lesions, affecting both the skin and internal organs, especially the lungs. In the lungs, this fibrosis leads to interstitial lung disease (ILD), a major cause of death in SSc patients. ILD, which encompasses various lung diseases, is characterized by excessive buildup of extracellular matrix (ECM) in the lungs. This accumulation results in scar tissue formation and destruction of airspaces, leading to impaired gas exchange, poor oxygenation, and eventual lung failure. Despite new anti-fibrotic treatments, ILD progression often continues, leaving lung transplantation as the only option for many patients, including those with SSc-ILD, despite its low five-year survival rate. This highlights the urgent need for new SSc-ILD treatments. A critical aspect of lung fibrosis is the transformation of fibroblasts into myofibroblasts, leading to excessive ECM deposition. Our lab has discovered an increase in genes responsible for ribosomal protein production, a key part of ribosome biogenesis (RiBi) in SSc-ILD and in experimental models of lung fibrosis. RiBi promotes cell proliferation and increased mRNA translation, contributing to a unique set of actively translated transcripts known as the translatome. Our preliminary data shows a distinct translatome in SSc-ILD fibroblasts compared to normal cells. Therefore, we hypothesize that in SSc-ILD, enhanced RiBi leads to an altered translatome that drives lung fibrosis. We will test this hypothesis using lung tissues and cells from individuals with SSc-ILD and relevant animal models. These will be used to identify the mechanisms that lead to increased RiBi and evaluate how the altered translatome promotes lung fibrosis. Completion of this proposal will establish the role of the ribosome in the pathophysiology of SSc-ILD and identify novel treatment strategies for this disease.