ABSTRACT Systemic sclerosis (SSc; scleroderma) is an idiopathic disorder of connective tissue characterized by increased production and deposition of collagen in the skin and internal organs such as the lungs. The etiology of SSc is unknown, although the role of genetic influences, environmental insults and abnormal immune function are subjects of active investigation. Interstitial lung disease (ILD) is a complication of SSc and is currently the leading cause of death in patients with this disease. Idiopathic pulmonary fibrosis (IPF) is also a fibrotic disease with high morbidity and mortality. We have a unique resource consisting of lung tissues from normal donors, patients with SSc and patients with IPF as well as matching primary lung fibroblasts. We have used the lung tissues to generate tissue microarrays (TMAs) that include normal lung, SSc lung, and IPF lung cores on the same TMA. We hypothesize that alteration of the collagen proteomes, including post- translational modifications, represents a novel and clinically relevant signature of pulmonary complications of SSc and IPF. We further hypothesize that very specific sites of collagen hydroxylation regulate the response of primary adult human lung fibroblasts. We propose to use a novel collagen-targeting proteomic approach to localize and measure collagen types and post- translational modifications within the lung tissues and identify disease (SSc vs. IPF) and phenotype (normal vs. fibrosis) changes. Identified post-translationally modified collagen peptides will be synthesized to test the response of fibroblasts from normal, SSc and IPF lung tissues to the peptides. Our findings will facilitate the development of targeted therapies and will also support the identification of novel biomarkers for pulmonary fibrosis.