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.

项目摘要/摘要肺炎高血压（POPH）是发生的一种肺动脉高压（PAH）仅在潜在的肝病患者中。 POPH表现出最高的发病率和死亡率 PAH亚型，影响所有慢性肝病患者的10％，但驱动疾病的机制发病机理知之甚少。肝门高血压和肝细胞功能障碍被认为是通过重要途径（例如血管）的失调，导致POPH中的血管重塑内皮生长因子（VEGF）信号传导。临床中使用的当前诊断和预后生物标志物练习（循环大脑纳位肽，BNP）是压力升高的非特异性标记与疾病严重程度（平均肺动脉压，MPAP和肺血管相关） POPH中的电阻，PVR）。因此，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。下一代测序可以隔离和研究相关的星状和 POPH中的内皮细胞群可能会影响重要的信号通路（例如VEGF）和有助于POPH的发病机理。该NIH K23提案的目的是使用综合综合的多学科方法接下来具有生物座验验证的肝组织的生成测序分析，以发展新型POPH特异性具有诊断和预后价值的循环肽生物标志物。我们将通过应用来实现这一目标对肝组织的单核RNA测序以及来自POPH和非poph肝硬化患者的血清样品，专注于生物学上合理的途径，例如VEGF信号，以识别新型疾病特异性的途径生物标志物。我们将使用从现有的生物样品和临床数据验证这些生物标志物大型良好的型疾病生物疗法，例如PAH国家生物样本和数据存储库。我们的初步数据已经确定了循环的VEGF1受体蛋白（FLT1）和蛋白激酶 Cα亚基（PRKCA）是具有诊断价值的有前途的POPH特异性候选生物标志物。使用 BNP作为比较器，我们将完成以下目的：目标1 - 确定差异基因表达 Poph内皮和星状细胞的； AIM 2 - 开发FLT1和PRKCA作为能够歧视的生物标志物来自肝肝硬化的POPH并评估POPH疾病的严重程度； AIM 3 - 开发FLT1和PRKCA作为预测 POPH中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以及临床意义。成功的这些目标的完成将开发具有临床价值的新型POPH特异性生物标志物，训练候选人进一步开发这些生物标志物作为POPH中的风险分层工具和治疗目标，最终改善由于肝病引起的肺血管疾病患者的临床护理。