Speaker: Stephen Y. Chan

When: 12:00pm, Nov 9, 2022

Where: ECE Conference Room 315D & Webinar/Zoom [ Join Meeting ]

Abstract

Vascular inflammation critically regulates endothelial pathophenotypes, yet causative mechanisms remain incompletely defined, particularly in pulmonary arterial hypertension (PAH). Immune dysregulation and metabolic reprogramming are recognized tenets of PAH pathogenesis, but a unifying theory connecting the two has not been established. Across in vitro and in vivo discovery platforms, we found that endothelial induction of the nuclear receptor coactivator 7 (NCOA7) tempered the generation of proinflammatory sterols by bolstering lysosomal acidification and constraining endothelial cell immunoactivation. Conversely, reduced NCOA7 promoted lysosomal dysfunction, resulting in sterol- and bile acid-driven inflammation and endothelial cell phenotypes consistent with PAH. In vivo, mice deficient for Ncoa7 or treated with a NCOA7-dependent inflammatory bile acid demonstrated worsened hemodynamic and histological indices of PAH. In parallel, an unbiased, metabolome-wide association study from the multicenter PAH Biobank cohort (N=2,666) identified the same NCOA7-dependent sterol and bile acid metabolite plasma signature as significantly associated with PAH mortality. Furthermore, the common variant intronic SNP rs11154337 in NCOA7 was found to control NCOA7 levels, lysosome activity, sterol and bile acid production, and EC immunoactivation in isogenic, CRISPR-Cas9, SNP-edited, iPSC-derived ECs, indicating a potentially widespread genetic predisposition to NCOA7 deficiency. Correspondingly, SNP rs11154337 was associated with PAH severity, as reflected by six-minute walk distance and mortality in a single-center PAH cohort (N=93). In a second validation, multi-center PAH cohort (N=826), SNP rs11154337 was further associated with mortality. Our work establishes a genetic and metabolic paradigm that links lysosomal biology and sterol and bile acid processes with EC inflammation. This paradigm carries broad implications not only on molecular diagnostic and therapeutic development in PAH but also in other vascular disorders 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.