This SCCOR application is focused on understanding the complex pulmonary vascular (PV) and right ventricular (RV) remodeling, resulting RV-PV uncoupling, and their crucial impact on morbidity and mortality in Pulmonary Arterial Hypertension (PAH). We will use scleroderma-associated PAH (PAH-SSc) as a clinical paradigm in this application, contrasting it to idiopathic PAH (IPAH), because of its particular severity, lack of response to available PAH therapy, and potential underlying genetic factors that dictate outcome. Because of our extensive PAH-SSc population and our expertise in molecular and diagnostic pulmonary medicine and cardiology, we have the unique opportunity to not only characterize RV-PV responses in PAH-SSc with increased sensitivity and clarity, but to also identify new molecular targets for potential therapy using state of the art imaging, genomic and proteomic technology. Relying on novel imaging systems and molecular tools, we propose to conduct rigorous phenotypic characterization of PAHSSc patients. Focused animal models will provide us with additional candidate genes and proteins for characterization and targeting in human studies. We will then validate the clinical importance of these genes in a large cohort of well-phenotyped patients with PAH, using functional genomics and proteomic approaches with characterization of potentially important polymorphisms. These data will provide new insights into the molecular basis for rational strategies for PAH-SSc patients, and elucidate the relationship of RV-PV dysfunction to the activation of pathological gene expression in genetically susceptible patients. The Hopkins SCCOR application represents a consortium of investigators with multi-disciplinary expertise, and the common goal to utilize state-of-the-art physiological, molecular, and genomic and proteomic approaches as well as novel phenotyping instrumentation that will provide the deepest understanding of the critical pathobiologic processes of RV-PV dysfunction and uncoupling to date, and define key genetic determinants relevant to PAH-SSc. Supported by six highly interactive cores (Administration, Data Management/Bioinformatics, Molecular Pathology, Genomic and Genotyping, Proteomics, and Imaging), the five human and animal projects will utilize novel phenotyping instrumentation and state of the art molecular approaches to PAH-SSc. We anticipate our work will provide a foundation for meaningful translational research that will facilitate development of new strategies, uncover therapeutic targets, and define new biomarkers and prognostic indicators that will limit the current dismal outcome of scleroderma-associated PAH.
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