PROGRAM SUMMARYPulmonary vascular disease (PVD) is perhaps the most important complication for children with congenital heartdisease (CHD) that results in increased pulmonary blood flow (PBF) and pressure. Postnatally the presence oflarge communications at the level of the ventricles (e.g. ventricular septal defect) or great vessels (e.g. truncusarteriosus) exposes the pulmonary circulation to abnormal elevations in blood flow and pressure which resultsin progressive structural and functional abnormalities of the pulmonary vasculature. Metabolic reprogramming isincreasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascularmorphology studies in our Shunt lamb model demonstrate a >2-fold increase in pulmonary arterioles in Shuntcompared to control lambs. This is opposed to the decrease in arterial counts demonstrated in humans withadvanced disease. This early increase in angiogenesis likely represents an adaptation to the increase in flowand pressure. The development of a hyperproliferative anti-apoptotic endothelial phenotype is necessary for thisangiogenic response. Further it requires a dramatic metabolic reprogramming that serves to supply these cellswith the necessary biosynthetic precursors required for cell division while simultaneously decreasing cellularATP levels due to increased consumption and decreased respiration. We have linked this decrease in ATP tothe loss of hsp90-mediated NO signaling and the development of endothelial dysfunction and vascularremodeling. Thus this PPG intensely focuses on increasing our understanding of: i) the differential effects ofmechanical forces on cellular metabolic programming; ii) post translational modifications (PTMs) that influencekey signaling pathways involved in metabolic reprogramming; iii) interactions between mitochondrial networkdynamics metabolism and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NOsignaling; and v) novel therapeutic strategies for treating CHD with increased PBF. The key novel pathways thatcomprise the focus of each Project were identified by our intensive investigations into the metabolicreprogramming underlying the development of pulmonary vascular disease and selected for their capacity tocontribute to a spectrum of cellular responses related to glutaminolysis and aerobic glycolysis (Project #1)cellular -oxidation and mitochondrial bioenergetics (Project #2) mitochondrial network dynamics andmitophagy (Project #3) and cell proliferation and apoptosis (Projects #1 & #3). Investigations are integratedacross our three PPG projects to fully understand how metabolic reprogramming leads to the loss of hsp90-mediated NO signaling and represents the thematic underpinning of this PPG. The synergy derived from theinteractions between individual Projects and scientific Cores with our programmatic approaches will promotean increased understanding of how mechanical forces modify cell metabolism NO signaling and endothelialfunction and the development of novel individualized therapies to attenuate pulmonary vascular disease inchildren born with CHD that result in increased PBF and pressure.