Sunday, May 11, 2025
5/11/2025
Cholesterol Regulation of EGFR-dependent Vasoconstriction in Chronic Hypoxia-induced Pulmonary Hypertension - Project Summary Chronic Hypoxia (CH)-induced pulmonary hypertension (PH) is a significant source of morbidity and mortality in patients with chronic obstructive pulmonary diseases. It is widely recognized that vasoconstriction is a critical mediator of PH, although the mechanisms involved are poorly understood. Our previous studies have demonstrated that enhanced vasoconstrictor sensitivity following CH involves a requisite reduction in pulmonary arterial smooth muscle cell (PASMC) membrane cholesterol content. We have also demonstrated that CH augments vasoconstrictor reactivity by a switch in signaling from primarily calcium-dependent mechanisms to a Ca2+ sensitization pathway that involves the epidermal growth factor receptor (EGFR) and reactive oxygen species (ROS). However, the mechanisms by which CH decreases membrane cholesterol and how this unmasks EGFR-dependent vasoconstriction has yet to be assessed. The proposed studies will investigate the central hypothesis that coupling of vasoconstrictor stimuli to EGFR signaling following CH promotes PASMC hypercontractility through a ROS-dependent decrease in membrane cholesterol. To test this hypothesis, protocols will employ both in vivo and in vitro approaches using a variety of experimental preparations from molecular and single cell imaging studies to video-microscopy of pressurized small pulmonary arteries using a rat model of CH-induced PH. We plan to pursue the following specific aims: Specific Aim 1: Determine the mechanism by which CH decreases PASMC membrane cholesterol. Hypothesis: Elevated ROS production during CH diminishes membrane cholesterol. Specific Aim 2: Determine the mechanism by which decreased PASMC membrane cholesterol augments vasoconstrictor sensitivity following CH. Hypothesis: Decreased PASMC membrane cholesterol in response to CH unmasks EGFR-dependent pulmonary vasoconstriction through regulation of NOX2 and Rac1. The applicant will be immersed in a rich training environment in the Vascular Physiology Group at the UNM School of Medicine through a unique, multi-sponsor mentoring team that will facilitate his research training in defining novel mechanisms by which ROS alter the PASMC membrane microenvironment to affect cellular function in CH-induced PH. The proposed training plan will afford the applicant intensive training experiences in a variety of new experimental approaches, refinement of his oral and written communication skills, and professional development training that will aid him in achieving his goal as an independent, academic physician-scientist in pulmonary research.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).