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Biomarker Discovery in Portopulmonary Hypertension

Award Number: K23HL164971
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/21/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Biomarker Discovery in Portopulmonary Hypertension - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $204,228 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Lung Diseases Research	000	3	2/27/2025	NON-COMPETING CONTINUATION	$204,228
														Subtotal = $204,228

Issue Date FY: 2024 ( Subtotal = $205,686 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Lung Diseases Research	000	2	4/9/2024	NON-COMPETING CONTINUATION	$205,686
														Subtotal = $205,686

Issue Date FY: 2023 ( Subtotal = $208,386 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Lung Diseases Research	000	1	4/21/2023	NEW	$208,386
														Subtotal = $208,386

Grand Total All Awards = $618,300

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Biomarker Discovery in Portopulmonary Hypertension

Award Number: K23HL164971

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/21/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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