Early Detection of Scleroderma-Associated Pulmonary Arterial Hypertension

硬皮病相关肺动脉高压的早期发现

• 批准号: 8822018
• 负责人: Scott Hall Visovatti
• 金额: $ 15.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822018
• 关键词: Address; Adenosine; Affect; Algorithms; Autoimmune Process; Bicycling; Bioinformatics; Biological Markers; Biology; Blood; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Categories; Cause of Death; Cell surface; Clinic; Clinical; Collaborations; Complex; Connective Tissue Diseases; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early treatment; Echocardiography; Elements; Endothelial Cells; Enzymes; Ergometry; Evaluation; Exercise; Fibrosis; Funding; Goals; Heart; Heart failure; Individual; Inflammation; K-Series Research Career Programs; Laboratories; Lead; Learning; Leukocytes; Longitudinal Studies; Lung; Measures; Mediating; Medical; Mentors; Mentorship; Michigan; Molecular Profiling; Monitor; National Heart, Lung, and Blood Institute; Nucleotidases; Nucleotides; Outcome; Participant; Patient Recruitments; Patients; Peer Review; Physicians; Physiological; Pilot Projects; Plasma; Primary Prevention; Protein Dephosphorylation; Publishing; Pulmonary Capillary Wedge Pressure; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary function tests; Purine Nucleotides; Recording of previous events; Records; Research; Research Personnel; Rest; Right Ventricular Function; Risk; Role; Scleroderma; Staging; Strategic Planning; Surface; Survival Rate; Systemic Scleroderma; Testing; Thrombosis; Time; Training; Training Programs; United States National Institutes of Health; Universities; Vascular Diseases; Ventricular; base; career; clinically relevant; data management; design; disease phenotype; healthy volunteer; hemodynamics; high risk; improved; metabolomics; novel; novel marker; nucleotidase; patient oriented research; pressure; programs; public health relevance; pulmonary arterial hypertension; research clinical testing; screening; tool

 DESCRIPTION (provided by applicant): Scleroderma, or systemic sclerosis (SSc), is an autoimmune connective tissue disorder characterized by inflammation, fibrosis and vasculopathy. Right heart failure caused by pulmonary arterial hypertension (PAH) is the leading cause of death in individuals with SSc, and approximately 10 to 15% of individuals with SSc will develop associated PAH (SSc-PAH). The combination of medical treatment options and systematic, routine screening has improved two-year survival for SSc-PAH, yet current screening tools are inadequate and the condition continues to remain under-diagnosed until it is too late. Preliminary data I have obtained demonstrate that even though resting PA pressures may be normal in SSc-PAH patients, hemodynamic evaluation during bicycle ergometry may unveil occult PAH. In fact, my preliminary data show 12 % of SSc patients with normal resting intra-cardiac pressures developed exercise pulmonary hypertension (mean pulmonary artery pressure e25 mmHg, pulmonary capillary wedge pressure d15 mmHg). In order to understand potential mechanisms which may contribute to the development of PAH, our laboratory has focused on the role of specific cell surface enzymes responsible for the catalytic degradation of purine nucleotides, which my mentor's group has shown to be critical regulators of thrombosis and inflammation at the vessel wall/blood interface. One of these "ectoenzymes," CD39, is found on the surface of endothelial cells and leukocytes. In my own published data, I have shown that CD39 can be specifically measured on plasma microparticles obtained from patients with PAH. In fact, these microparticles retain their catalytic activity, and are surprisingly elevaed in patients with PAH compared with controls.6 My preliminary data also indicates that alterations in the concentrations of plasma nucleotides and adenosine (the CD39-mediated metabolites of ATP dephosphorylation) may contribute to pulmonary hypertension. These preliminary data lead me to hypothesize that a combination of early hemodynamic factors, right ventricular strain, and circulating plasma biomarkers can be used to identify patients with sub-clinical SSc-PAH who are at risk for the development of overt SSc-PAH. This proposal will study 225 patients with SSc who are at risk for developing PAH, as well as 75 healthy controls, to determine the extent to which hemodynamic parameters, echocardiographic markers of RV strain, and novel plasma microparticle and nucleotide biomarkers obtained at rest and during exercise can predict the development of SSc-PAH. I will complete this project under the mentorship of physician researchers with domain expertise in vascular biology, pulmonary arterial hypertension, SSc, biomarkers and bioinformatics, all of whom have strong track records of training and peer-reviewed funding. My project and relevant didactic coursework will serve as a training vehicle for me during this career development award by enabling me to learn elements of patient recruitment, data management, statistical analysis, acquisition/interpretation of meaningful hemodynamic and echocardiographic research data, and laboratory based analysis of plasma-based biomarkers of disease progression. This program, including didactic, immersive, and mentored components, will prepare me for an independent research career in patient-oriented research.

 描述（由申请人提供）：硬皮病或系统性硬化症（SSc）是一种自身免疫性结缔组织疾病，其特征为炎症、纤维化和血管病变。肺动脉高压（PAH）引起的右心衰竭是SSc患者死亡的主要原因，大约10 - 15%的SSc患者会发生相关PAH（SSc-PAH）。医学治疗方案和系统性常规筛查的结合提高了SSc-PAH的两年生存率，但目前的筛查工具不足，病情继续被诊断不足，直到为时已晚。我获得的初步数据表明，即使SSc-PAH患者的静息PA压力可能正常，但自行车测力计期间的血流动力学评价可能揭示隐匿性PAH。事实上，我的初步数据显示，12%的静息心内压正常的SSc患者发生了运动性肺动脉高压（平均肺动脉压e25 mmHg，肺毛细血管楔压d15 mmHg）。为了了解可能有助于PAH发展的潜在机制，我们的实验室专注于负责嘌呤核苷酸催化降解的特定细胞表面酶的作用，我的导师的团队已经证明嘌呤核苷酸是血管壁/血液界面血栓形成和炎症的关键调节剂。这些“胞外酶”中的一种，CD 39，在内皮细胞和白细胞的表面上发现。在我自己发表的数据中，我已经表明，CD 39可以在PAH患者的血浆微粒上特异性测量。事实上，这些微粒保留了它们的催化活性，并且与对照组相比，PAH患者中的微粒含量令人惊讶地升高。6我的初步数据还表明，血浆核苷酸和腺苷（CD 39介导的ATP去磷酸化代谢物）浓度的改变可能导致肺动脉高压。这些初步数据使我假设，早期血流动力学因素、右心室应变和循环血浆生物标志物的组合可用于识别有明显SSc-PAH发展风险的亚临床SSc-PAH患者。该提案将研究225例有发生PAH风险的SSc患者以及75例健康对照，以确定血流动力学参数、RV株的超声心动图标记物以及在静息和运动期间获得的新型血浆微粒和核苷酸生物标志物可预测SSc-PAH发生的程度。我将在具有血管生物学、肺动脉高压、SSc、生物标志物和生物信息学领域专业知识的医生研究人员的指导下完成这个项目，他们都有良好的培训和同行评审资金记录。我的项目和相关教学课程将作为我在这个职业发展奖的培训工具，使我能够学习患者招募，数据管理，统计分析，有意义的血液动力学和超声心动图研究数据的采集/解释，以及基于血浆的疾病进展生物标志物的实验室分析。该计划，包括教学，沉浸式和辅导组件，将准备我在以患者为导向的研究独立的研究生涯。