Biomarker Discovery in Portopulmonary Hypertension

门脉性肺动脉高压的生物标志物发现

基本信息

批准号：
10663708
负责人：
Arun Jose
金额：
$ 20.84万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-21 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663708
关键词：
Address Affect Animal Model Arterial Disorder Benchmarking Biological Biological Assay Biological Markers Blood Vessels Bone Morphogenetic Proteins Brain natriuretic peptide Cardiac Catheterization Procedures Cardiovascular Diseases Cirrhosis Clinical Clinical Data Clinical Research Collaborations Data Data Analyses Dedications Deterioration Development Development Plans Diagnosis Diagnostic Disease Disease Marker Early Diagnosis Early treatment Endothelial Cells Ensure Environment Epidemiology Estrogen Metabolism Estrogens Exhibits FLT1 gene Foundations Functional disorder Future Gene Expression Genes Goals Hepatic Hepatic Stellate Cell Incidence Institution Knowledge Liver Liver Cirrhosis Liver Dysfunction Liver diseases Longitudinal cohort Lung Lung diseases Measures Mentors Modeling Molecular Morbidity - disease rate Natriuretic Peptides Nuclear RNA Outcome PRKCA gene Pathogenesis Pathway interactions Patient Care Patient-Focused Outcomes Patients Peptides Population Portal Hypertension Prevalence Prognosis Prognostic Marker Protein Secretion Proteins Public Health Pulmonary Vascular Resistance Regulation Research Research Project Grants Resources Sampling Serum Severity of illness Signal Pathway Signal Transduction Specificity Testing Therapeutic Tissue Banks Tissue-Specific Gene Expression Tissues Training Translational Research United States National Institutes of Health Validation Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular remodeling Work accurate diagnosis aggressive therapy angiogenesis biobank biomarker discovery biomarker validation candidate identification candidate marker career development chronic liver disease clinical care clinical practice clinically significant cohort data repository diagnostic biomarker diagnostic value differential expression disease phenotype experience high risk population hypertensive improved improved outcome interdisciplinary approach liver transplantation mortality next generation sequencing novel novel diagnostics novel marker participant enrollment portopulmonary hypertension predictive marker pressure prognostic performance prognostic value prognostication prospective pulmonary arterial hypertension pulmonary arterial pressure pulmonary vascular disorder pulmonary vascular remodeling receptor response risk stratification specific biomarkers stellate cell success targeted treatment therapeutic target tool transcriptome sequencing transcriptomics treatment response

项目摘要

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.

项目概要/摘要门脉性肺动脉高压 (PoPH) 是肺动脉高压 (PAH) 的一种，发生于仅在患有潜在肝病的患者中，PoPH 的发病率和死亡率最高。 PAH 亚型，影响 10% 的慢性肝病患者，但驱动疾病的机制人们对肝门静脉高压和肝细胞功能障碍的发病机制知之甚少。通过重要通路（如血管）的失调，促进 PoPH 中的血管重塑内皮生长因子 (VEGF) 信号传导目前用于临床的诊断和预后生物标志物。实践（循环脑钠肽，BNP）是血压升高和弱的非特异性标志物与疾病严重程度相关（平均肺动脉压、mPAP 和肺血管抗性（PVR）在 PoPH 中进行测试，迫切需要开发新的 PoPH 特异性生物标志物。具有诊断和预后价值的下一代测序可以分离和研究相关的星状和 PoPH 中的内皮细胞群，可能影响重要的信号通路（例如 VEGF）和有助于 PoPH 的发病机制。 NIH K23 提案的目的是使用多学科方法结合综合下一步通过生物样本库验证对肝组织进行世代测序分析，以开发新型 PoPH 特异性我们将通过应用具有诊断和预后价值的循环肽生物标志物来实现这一目标。对 PoPH 和非 PoPH 肝硬化患者的肝组织和血清样本进行单核 RNA 测序，专注于生物学上合理的途径，例如 VEGF 信号传导，以识别新的疾病特异性我们将使用从现有获得的生物样本和临床数据来验证这些生物标记。大型表型良好的疾病生物样本库，例如 PAH 国家生物样本和数据我们的初步数据已鉴定出循环 VEGF1 受体蛋白 (FLT1) 和蛋白激酶。 C Alpha 亚基 (PRKCA) 作为一种有前景的 PoPH 特异性候选生物标志物，具有诊断价值。 BNP作为比较器，我们将完成以下目标：目标1——确定差异基因表达 PoPH 内皮细胞和星状细胞；目标 2 – 开发 FLT1 和 PRKCA 作为能够区分的生物标志物肝硬化中的 PoPH 并评估 PoPH 疾病的严重程度；目标 3 – 开发 FLT1 和 PRKCA 作为预测指标 PoPH 治疗反应的生物标志物该项目与公共卫生高度相关，因为 PoPH 和慢性肝病的发病率和患病率增加及其临床意义。完成这些目标将开发具有临床价值的新型 PoPH 特异性生物标志物，培训候选人进一步开发这些生物标志物作为 PoPH 的风险分层工具和治疗靶点，并最终改善肝病引起的肺血管疾病患者的临床护理。