Abstract

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, yet causative mechanisms remain incompletely defined, particularly in pulmonary arterial hypertension (PAH). Both lysosomal activity and cholesterol metabolism have been linked to cellular inflammation in other contexts, but the relevance to PAH is unclear. Supported by genomic and metabolomic association analyses of mortality in PAH across >3,000 patients in total, we have established a paradigm whereby allele-specific SNP regulation of endosomal lysosomal acidification controls sterol and bile acid metabolism, downstream inflammation, and PAH severity. Using computational algorithms to predict protein target druggability, we have identified and experimentally validated a small molecule that targets lysosomal acidification and reduces inflammation in PAH as well as other conditions of viral and bacterial infections of the lung. This paradigm defines a specific genetic and metabolic predisposition to PAH and carries implications for diagnostic and therapeutic development in PAH as well as in other conditions dependent upon acquired and innate immune regulation.

Speaker Bio

Stephen Chan, MD, PhD, is the Vitalant Chair in Vascular Medicine and Professor of Medicine (Cardiology) at the University of Pittsburgh School of Medicine. He serves as the Director of the Vascular Medicine Institute, a multi-disciplinary research institute with 40 primary and associated investigators and with $25M of yearly research expenditures. Dr. Chan also leads a basic science and translational research laboratory studying the molecular mechanisms of pulmonary vascular disease and pulmonary hypertension (PH) – a disease where reductionistic studies have primarily focused on only end-stage molecular effectors. To capitalize on the emerging discipline of “network medicine,” the Chan laboratory utilizes a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodent and human subjects to accelerate systems-wide discovery in PH. In doing so, Dr. Chan’s published work was the first to identify the systems-level importance of microRNAs as a root cause for pulmonary hypertension, controlling metabolism, inflammation, and vascular stiffness. Dr. Chan’s recent work also delves into the computational biology of -omics datasets in order to predict unique pathogenic pathways important in PH. Dr. Chan has served as Chair of the NIH Respiratory Integrative Biology and Translational Research (RIBT) study section, holds multiple grants from the NIH, is an elected member of the American Society for Clinical Investigation, and holds an Established Investigator Award from the American Heart Association.