Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY/ABSTRACT Portopulmonary Hypertension (PoPH) is a type of pulmonary arterial hypertension (PAH) that occurs exclusively in patients with underlying liver disease. PoPH exhibits the highest morbidity and mortality of all PAH subtypes, affecting 10% of all chronic liver disease patients, but the mechanisms that drive disease pathogenesis are poorly understood. Liver portal hypertension and hepatocellular dysfunction are believed to contribute to vascular remodeling in PoPH through dysregulation of important pathways such as vascular endothelial growth factor (VEGF) signaling. The current diagnostic and prognostic biomarker used in clinical practice (circulating brain natriuretic peptide, BNP) is a nonspecific marker of elevated pressure and weakly correlated with disease severity (mean pulmonary arterial pressure, mPAP, and pulmonary vascular resistance, PVR) in PoPH. Consequently, there is a critical need to develop new PoPH-specific biomarkers with diagnostic and prognostic value. Next generation sequencing can isolate and study relevant stellate and endothelial cell populations in PoPH, that are likely to affect important signaling pathways (such as VEGF) and contribute to the pathogenesis of PoPH. The purpose of this NIH K23 proposal is to use a multidisciplinary approach combining integrated next generation sequencing analysis of liver tissue with biorepository validation to develop novel PoPH-specific circulating peptide biomarkers with diagnostic and prognostic value. We will accomplish this goal by applying single nuclear RNA sequencing to liver tissue and serum samples from PoPH and non-PoPH cirrhotic patients, focusing on biologically plausible pathways such as VEGF signaling, to identify novel disease-specific biomarkers. We will validate these biomarkers using biological samples and clinical data obtained from existing large well-phenotyped disease biorepositories such as the PAH National Biological Sample and Data Repository. Our preliminary data has identified circulating VEGF1 receptor protein (FLT1) and Protein Kinase C Alpha subunit (PRKCA) as a promising PoPH-specific candidate biomarkers with diagnostic value. Using BNP as a comparator, we will complete the following aims: Aim 1– Determine the differential gene expression of PoPH endothelial and stellate cells; Aim 2 – Develop FLT1 and PRKCA as biomarkers able to discriminate PoPH from liver cirrhosis and assess PoPH disease severity; Aim 3 – Develop FLT1 and PRKCA as predictive biomarkers of treatment response in PoPH. This project is highly relevant to public health because of the increasing incidence and prevalence, and clinical significance of PoPH and chronic liver disease. Successful completion of these aims will develop novel PoPH-specific biomarkers with clinical value, train the candidate to further develop these biomarkers as risk-stratification tools and therapeutic targets in PoPH, and ultimately improve the clinical care of patients with pulmonary vascular disease due to liver disease.
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).
