The goal of this R21 proposal is to provide preliminary data on a novel application of phage display aimed at uncovering serum markers of severe pulmonary hypertension (SPH) that are concordant with those identified in situ in remodeled pulmonary arteries. SPH is an irreversible, malignant elevation of pulmonary artery pressures, often associated with high mortality due to right side heart failure. The delay in diagnosis imparts limited response to a handful of therapeutic options presently available. Identification of biomarkers of the disease would significantly aid in early diagnosis of SPH and to monitor therapeutic responses. We hypothesize that vascular markers unique to pulmonary artery remodeling in SPH, shed from the pulmonary vasculature and are represented in the serum of patients with SPH. We propose to uncover these unique tissue and serum disease markers using phage display methodology. The proposal relies on human lung tissue of patients with SPH banked by the PI and on blood samples either banked by the Hopkins Program in Genomics Application or to be collected throughout the course of the present study. Two aims are proposed: 1. To define endothelial cell or smooth muscle phenotypic markers of SPH using phage display, using state of the art laser micro-dissected smooth muscle or endothelial cell samples of PPH lungs; and 2. To define serum markers unique to patients with SPH, as compared to mild PH or control patients, which are also represented in the remodeled pulmonary arteries, using phage display of PPH serum ligands. We believe that our proposal fulfils the critical requirements that guide the R21 award in that it is innovative, it may have a potential high impact in the diagnosis and management of SPH and on novel approaches aimed at finding markers of other lung diseases, such as interstitial lung diseases or sarcoidosis, and may lead to novel venues of investigation of pathobiology of lung disease.