The role of xanthine oxidoreductase activity and altered metabolism in scleroderma-associated pulmonary arterial hypertension

黄嘌呤氧化还原酶活性和代谢改变在硬皮病相关肺动脉高压中的作用

• 批准号: 10039193
• 负责人: Catherine Simpson
• 金额: $ 17.66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10039193
• 关键词: Address; Affect; Allopurinol; Animal Model; Apoptosis; Biochemical Reaction; Biological; Biological Assay; Biological Markers; Cause of Death; Cell Death; Cessation of life; Clinical; Clinical Data; Clinical Research; Cluster Analysis; Complex; Data; Data Sources; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Endothelial Cells; Endothelium; Ensure; Environment; Enzymes; Failure; Functional disorder; Future; Generations; Heart failure; Human; Image; Infrastructure; Link; Longitudinal cohort; Lung; Measures; Mentors; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular Biology; Molecular Epidemiology; Morbidity - disease rate; Newly Diagnosed; Outcome; Oxidative Stress; Oxides; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Progressive Disease; Prospective cohort; Prospective cohort study; Proteins; Purines; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Right Ventricular Dysfunction; Right ventricular structure; Role; Sampling; Scleroderma; Serum; Severity of illness; Signal Transduction; Surrogate Markers; Survivors; Systemic Scleroderma; Therapeutic; Time; Training; Translational Research; United States National Institutes of Health; Uric Acid; Vascular Diseases; Vasomotor; Ventricular; Ventricular Remodeling; Work; XDH gene; activity marker; biobank; clinical epidemiology; clinical phenotype; disease phenotype; disorder risk; hemodynamics; high risk; improved outcome; insight; metabolomics; mortality; new therapeutic target; novel; novel marker; outcome prediction; oxidative damage; pre-clinical; prevent; prospective; pulmonary arterial hypertension; purine metabolism; response; skills; success; therapeutic target

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right heart failure and death. Patients with scleroderma (SSc) are at high risk for the development of PAH (SSc-PAH), which is a leading cause of death in SSc. While advances in PAH therapeutics have led to improved outcomes, survival in SSc-PAH remains dismal, with 57% of patients dying within 5 years of diagnosis. Thus, there is an urgent need to expand therapeutic options in SSc-PAH, and to identify novel markers of disease risk and severity. PAH pathogenesis is highly complex, with simultaneous dysregulation of multiple biologic pathways, yet current therapies for PAH target just three pathways that regulate vasomotor tone. One potentially targetable metabolic regulator is the protein xanthine oxidoreductase (XOR), which metabolizes purines in an enzymatic reaction that generates uric acid and reactive oxygen species (ROS). Oxidative injury from over-abundant ROS drives endothelial cell dysfunction, altered metabolic signaling, and endothelial apoptosis, all early features of PAH pathobiology. XOR activity increases in experimental PH models, and XOR inhibition with allopurinol prevents pulmonary hypertensive changes from occurring. XOR activity is increased in PAH patients compared to healthy controls, and our preliminary data show that serum UA/XOR levels and purine metabolites significantly correlate with hemodynamics and predict outcomes in SSc-PAH patients. However, XOR has not been studied as a driver of disease and potential therapeutic target in SSc-PAH. We hypothesize that increased XOR activity contributes to PAH development in SSc and drives disease progression through oxidative injury and altered metabolism. By leveraging two rich data sources – the world's largest known SSc serum biorepository, and an NIH-sponsored prospective cohort of newly diagnosed SSc-PAH patients - we aim to 1) demonstrate that increased XOR activity and oxidative stress influence development of PAH in patients with scleroderma, 2) link XOR activity and oxidative stress with phenotypic and outcome data in SSc-PAH (with a special focus on right ventricular structural and functional phenotypes), and 3) identify metabolic patterns associated with poor clinical response to currently available PAH therapies. These aims will examine the role of XOR activity and oxidative stress in SSc-PAH in order to clarify the potential of XOR as a therapeutic target, and to lay a groundwork for personalized selection of PAH therapies in SSc.

项目总结/摘要 肺动脉高压（PAH）是一种进行性肺血管疾病，导致右肺动脉高压。 心力衰竭和死亡。硬皮病（SSc）患者发生PAH（SSc-PAH）的风险较高， 这是SSc的主要死因。虽然PAH治疗方法的进步导致了结局的改善， SSc-PAH的生存率仍然很低，57%的患者在诊断后5年内死亡。因此， 迫切需要扩大SSc-PAH的治疗选择，并确定疾病风险和严重程度的新标志物。 PAH发病机制高度复杂，同时存在多种生物学途径的失调，但目前 PAH的治疗仅针对调节血管紧张素的三种途径。一种潜在的靶向代谢 调节剂是蛋白质黄嘌呤氧化还原酶（XOR），其在酶促反应中代谢嘌呤， 产生尿酸和活性氧（ROS）。过量活性氧驱动的氧化损伤 内皮细胞功能障碍、代谢信号改变和内皮细胞凋亡，均为PAH的早期特征 病理生物学在实验性PH模型中，XOR活性增加，别嘌呤醇抑制XOR可防止 肺动脉高压的变化。与健康人相比，PAH患者的XOR活性增加 我们的初步数据显示，血清UA/XOR水平和嘌呤代谢产物显著相关， 并预测SSc-PAH患者的结局。然而，XOR尚未被研究为驱动程序 疾病和潜在的治疗靶点。 我们假设XOR活性增加有助于SSc中PAH的发展并驱动疾病 通过氧化损伤和代谢改变进展。通过利用两个丰富的数据源-世界上 已知最大的SSc血清生物储存库，以及NIH申办的新诊断的SSc-PAH前瞻性队列 患者-我们的目的是1）证明增加的XOR活性和氧化应激影响发展， 硬皮病患者的PAH，2）将XOR活性和氧化应激与硬皮病患者的表型和结局数据联系起来， SSc-PAH（特别关注右心室结构和功能表型），以及3）确定代谢 与目前可用的PAH治疗的临床应答差相关的模式。这些目标将审查 XOR活性和氧化应激在SSc-PAH中的作用，以阐明XOR作为治疗药物的潜力 目标，并为SSc中PAH治疗的个性化选择奠定基础。