CORE--MOLECULAR PATHOLOGY

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This SCCOR application is designed to investigate the mechanisms involved in right ventricular dysfunction. It proposes a comprehensive dissection of phenotypes of pulmonary hypertension using an extensive population of idiopathic pulmonary arterial hypertension (IPAH) and scleroderma-associated PAH (PAH-SSc) to define novel genes involved in the disease and develop biomarkers related to disease morbidity and mortality. The Molecular Pathology Core (Core C) will provide high quality tissue processing, accurate phenotypic characterization of right ventricular and pulmonary vascular remodeling, and state-of-the art tools to investigate and validate potential markers of disease and pathogenetically relevant molecules that may play a role on the impact of pulmonary hypertension in right ventricular dysfunction in pulmonary hypertension. We propose the following strategies to accomplish these goals: 1. To assist the investigators in all projects in the experimental design to facilitate examine pulmonary vascular and right ventricular alterations in pulmonary hypertension (Projects 1-5); 2. To collect, process, and catalogue human and animal lungs subjected to the different experimental manipulations, based on accrual of lungs obtained at the time of ex-plantation or lung tumor resection (Projects 1-3); 3. To define the morphological alterations present in lung tissue to be subjected to genomic and proteomics studies (in sporadic biopsies or autopsies, in Projects 1-3); 4. To perform immunohistochemical characterization of the pattern of lung distribution of markers and relevant proteins identified as important to the experiments outlined in Projects 1-5; 5. To perform in situ hybridization strategies at the transcript localization in lungs (Projects 1-5); 6. To correlate the protein and transcription data with morphological alterations present at the light microscopic level; and 7. To obtain cell and structure specific populations by laser micro-dissection for expression studies (Projects 1-5). Within the framework of discovery of biomarkers and genes associated with PAH, the Molecular Pathology Core will enable the validation of disease markers and candidate molecules in dysfunctional hearts and remodeled pulmonary arteries. Importantly, during the preparation of preliminary data for this proposal, this Core has demonstrated that its flexibility, expertise and resources are available and essential to all of the projects in the SCCOR proposal.