Common and distinct metabolic pathways of pulmonary sarcoidosis phenotypes and endotypes

PROJECT SUMMARY/ABSTRACT This research aims to identify common and distinct metabolic and proteomic pathways associated with inflammation and fibrosis in pulmonary sarcoidosis. Sarcoidosis is a multi-organ granulomatous disease, with at least 20% of patients suffering severe pulmonary fibrosis. Recent studies suggest a two-phase process for fibrotic sarcoidosis: the initial development of chronic inflammation, followed by transformation to fibrosis, potentially driven by profibrotic genes and persistent inflammation. However, the processes driving profibrotic versus inflammatory responses are unknown. Metabolomic and proteomic profiles, influenced by both genetics and environmental exposures, can capture this complex biological intersection in interstitial lung disease studies. Limited studies have identified dysregulated lipid, carbohydrate, amino acid, and TCA cycle metabolic pathways, as well as proteomic pathways associated with pulmonary fibrosis. However, understanding whether fibrotic and non-fibrotic pulmonary sarcoidosis share common metabolic and proteomic pathways related to fibrosis and/or immunity/inflammation remains a gap in knowledge. In our fibrotic sarcoidosis genome-wide and transcriptome- wide association study, we found PARN is a candidate driver for fibrotic sarcoidosis. Rare variants in PARN have been associated with familial pulmonary fibrosis and may be related to shortened telomeres. Additionally, we found the arginine availability index (AAI, Arginine/[Ornithine+Citrulline]) is lower in sarcoidosis cases vs. controls. Based on previous studies and our preliminary results, we hypothesize that distinct metabolic pathways differentiate fibrotic and non-fibrotic pulmonary sarcoidosis, with specific endotypes showing distinct clinical characteristics. We will use plasma specimens from two studies available at the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC): the A Case Controlled Etiologic Study of Sarcoidosis (ACCESS) and the Lung Tissue Research Consortium (LTRC) for pulmonary sarcoidosis (both fibrotic and non- fibrotic) patients, as well as healthy controls. All plasma samples will undergo metabolomic and proteomic profiling. Additionally, we will use the UK Biobank for multi-omics validation. Our specific aims are: 1) Identify common and distinct metabolic and proteomic pathways between fibrotic and non-fibrotic pulmonary sarcoidosis. 2) Define molecular endotypes among pulmonary sarcoidosis patients. Our long-term goal is to utilize blood metabolomic and proteomic signatures to identify individuals with pulmonary sarcoidosis at risk of developing fibrosis. This proposal will establish a framework for shared pathway analysis and facilitate future larger-scale prospective multi-center studies to identify biomarkers for fibrotic sarcoidosis and its progression.