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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

基本信息

批准号：
10670315
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
项目类别：
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/10670315
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 Dedications Development Diagnosis Disease Disease Outcome Disease Progression Endothelial Cells Endothelium Ensure Environment Enzymes Functional disorder Future Generations 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 Pathogenesis Pathway interactions Patients Pattern Phenotype Productivity Progressive Disease Prospective cohort Prospective, cohort study Proteins Purines Reactive Oxygen Species Research Research Personnel Research Project Grants Right Ventricular Dysfunction 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 Vasomotor Ventricular Work XDH gene activity marker biobank clinical epidemiology clinical phenotype disease phenotype disorder risk hemodynamics high risk hypertensive improved outcome insight metabolomics mortality new therapeutic target novel novel marker outcome prediction oxidative damage pre-clinical prevent prospective pulmonary arterial hypertension pulmonary vascular disorder purine metabolism response right ventricular failure right ventricular remodeling skills success therapeutic target

项目摘要

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.

项目摘要/摘要肺动脉高压(PAH)是一种进行性的肺血管疾病，导致右心力衰竭和死亡。硬皮病(SSC)患者患PAH(SSC-PAH)的风险很高，这是导致SSC死亡的主要原因。虽然PAH疗法的进步导致了结果的改善， SSc-PAH的存活率仍然很低，57%的患者在确诊后5年内死亡。因此，有一个迫切需要扩大SSc-PAH的治疗选择，并确定疾病风险和严重程度的新标记物。 PAH的发病机制非常复杂，同时存在多条生物通路的失调，但目前 PAH的治疗只针对调节血管舒缩张力的三条途径。一种潜在的靶向代谢调节因子是蛋白质黄嘌呤氧化还原酶(XOR)，它在酶促反应中代谢嘌呤，产生尿酸和活性氧(ROS)。过量的ROS驱动引起的氧化损伤血管内皮细胞功能障碍、代谢信号改变和内皮细胞凋亡，这些都是PAH的早期特征病理生物学。实验性PH模型中XOR活性增加，用别嘌醇抑制XOR可防止发生肺动脉高压改变。与健康人相比，PAH患者的XOR活性增加对照，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对SSc-PAH患者的血流动力学和预后进行预测。然而，XOR还没有被作为驱动程序进行研究 SSc-PAH的疾病和潜在的治疗靶点。我们假设，XOR活性的增加有助于SSc中PAH的发展并驱动疾病通过氧化损伤和新陈代谢改变而进展。通过利用两个丰富的数据源-世界上已知最大的SSC血清生物库，以及由NIH赞助的新诊断的SSC-PAH的预期队列患者-我们的目标是1)证明XOR活性增加和氧化应激影响硬皮病患者中的PAH，2)将XOR活性和氧化应激与表型和预后数据联系起来 SSC-PAH(特别关注右室结构和功能表型)，以及3)识别代谢与目前可用的PAH疗法临床反应差相关的模式。这些目标将检验 XOR活性和氧化应激在SSc-PAH中的作用以阐明XOR的治疗潜力为在SSC中个体化选择PAH疗法奠定基础。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Defining minimal detectable difference in echocardiographic measures of right ventricular function in systemic sclerosis.

DOI：
10.1186/s13075-022-02835-5
发表时间：
2022-06-18
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
通讯作者：

Pregnancy Considerations in the Multidisciplinary Care of Patients with Pulmonary Arterial Hypertension.

肺动脉高压患者的多学科护理中的怀孕考虑。

DOI：
10.3390/jcdd9080260
发表时间：
2022-08-11
期刊：
Journal of cardiovascular development and disease
影响因子：
2.4
作者：
通讯作者：

Right ventricular function as assessed by cardiac magnetic resonance imaging-derived strain parameters compared to high-fidelity micromanometer catheter measurements.

DOI：
10.1177/20458940211032529
发表时间：
2021-10
期刊：
Pulmonary circulation
影响因子：
2.6
作者：
Sato T;Ambale-Venkatesh B;Zimmerman SL;Tedford RJ;Hsu S;Chamera E;Fujii T;Mullin CJ;Mercurio V;Khair R;Corona-Villalobos CP;Simpson CE;Damico RL;Kolb TM;Mathai SC;Lima JAC;Kass DA;Tsujino I;Hassoun PM
通讯作者：
Hassoun PM

Ventricular mass discriminates pulmonary arterial hypertension as redefined at the Sixth World Symposium on Pulmonary Hypertension.

DOI：
10.1002/pul2.12005
发表时间：
2022-01
期刊：
PULMONARY CIRCULATION
影响因子：
2.6
作者：
Simpson, Catherine E.;Kolb, Todd M.;Hsu, Steven;Zimmerman, Stefan L.;Corona-Villalobos, Celia P.;Mathai, Stephen C.;Damico, Rachel L.;Hassoun, Paul M.
通讯作者：
Hassoun, Paul M.

The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension.

血管抑制肽内皮抑素增强了肺动脉高压的死亡风险预测。

DOI：
10.1183/23120541.00378-2021
发表时间：
2021
期刊：
ERJ open research
影响因子：
4.6
作者：
Simpson,CatherineE;Griffiths,Megan;Yang,Jun;Nies,MelanieK;Vaidya,RDhananjay;Brandal,Stephanie;Martin,LisaJ;Pauciulo,MichaelW;Lutz,KatieA;Coleman,AnnaW;Austin,EricD;Ivy,DDunbar;Nichols,WilliamC;Everett,AllenD;Hassoun,
通讯作者：
Hassoun,