Molecular imaging of angiogenic activity in pulmonary arterial hypertension

肺动脉高压血管生成活性的分子成像

• 批准号: 9313927
• 负责人: PAUL B YU
• 金额: $ 77.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313927
• 关键词: Affect; Anatomy; Binding; Biological Markers; Blood Vessels; Coupled; Coupling; Data; Development; Diagnosis; Disease; Disease Progression; Disease regression; Disease stratification; Distal; Early Diagnosis; Early Intervention; Etiology; Experimental Models; Gene Expression; Growth Factor; Heart failure; Histopathology; Human; Image; Intercept; Intervention; Investigational Therapies; Label; Laboratories; Lesion; Link; Lung; Methods; Modality; Modeling; Molecular; Monitor; Obstruction; Outcome; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plant Roots; Positron-Emission Tomography; Program Development; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary vessels; Radioisotopes; Rattus; Reporting; Resistance; Scanning; Sensitivity and Specificity; Severities; Severity of illness; Signal Transduction; Techniques; Telemetry; Testing; Tissues; Transforming Growth Factor beta; Transplantation; Validation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Vasodilator Agents; X-Ray Computed Tomography; arteriole; base; bevacizumab; conventional therapy; disease natural history; disorder control; effective intervention; effective therapy; ex vivo perfusion; experimental study; hemodynamics; humanized monoclonal antibodies; imaging agent; imaging modality; imaging probe; improved; improved outcome; insight; lung imaging; man; molecular imaging; mortality; non-invasive imaging; novel; novel therapeutic intervention; novel therapeutics; overexpression; preclinical development; preclinical study; pressure; programs; pulmonary arterial hypertension; targeted imaging; tool; treatment response; uptake; validation studies; vascular bed

 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive thickening and obliteration of resistance-determining vessels of the pulmonary circulation. Despite current therapies, survival following the diagnosis of PAH remains approximately 50% at 5 years, with mortality a result of disease progression and right heart failure. Delayed diagnosis, the lack of more direct biomarkers of disease activity, and the lack of treatments that can arrest or reverse pulmonary vascular remodeling are all barriers to improved outcomes in PAH. A sensitive, non-invasive imaging test that directly monitors pulmonary vascular disease activity could help expedite diagnosis and identify effective interventions. This proposal will validate the utility of a novel positron emission tomography (PET) molecular imaging modality, using 89Zr-bevacizumab to detect pathologic VEGF activity in the vessels affected by PH. Preliminary data demonstrates that PET imaging using 89Zr- bevacizumab detects enhanced VEGF activity in the distal circulation of the pulmonary vasculature in experimental PAH, and has the potential to recognize active lesions of remodeling in human PAH. These studies will directly test whether or not PET 89Zr- bevacizumab imaging can detect early disease, prior to the development of significant vessel loss and hemodynamically significant PAH, predict the severity and progression of disease, and reflect the ability of approved vasodilator and novel therapeutic interventions to intercept angiogenic remodeling activity in the pulmonary circulation. Validation studies will be performed using living, explanted human lungs affected by PAH using an ex-vivo perfusion approach, to raise confidence in the translatability of these findings. The validation of this approach would constitute a breakthrough in our ability to assess ongoing remodeling in a vascular bed which is ordinarily inaccessible to clinicians, to allow objective stratification of disease severity and rik, tailor pharmacotherapy based on disease activity, and potentially identify therapies acting by entirely novel mechanisms to arrest or reverse disease progression. (End of Abstract)

 描述(由申请人提供)： 肺动脉高压(PAH)是一种肺血管阻力升高的疾病，其特征是肺循环中决定阻力的血管进行性增厚和闭塞。尽管有目前的治疗方法，诊断为PAH后的存活率在5年内仍保持在约50%，死亡率是疾病进展和右心衰竭的结果。延误的诊断，缺乏更直接的疾病活动性生物标志物，以及缺乏可以阻止或逆转肺血管重构的治疗，这些都是改善PAH预后的障碍。一种灵敏的、非侵入性的成像测试可以直接监测肺血管疾病的活动，有助于加快诊断和确定有效的干预措施。这项建议将验证一种新的正电子发射断层扫描(PET)分子成像方式的实用性，使用89Zr-贝伐单抗来检测受PH影响的血管中的病理血管内皮生长因子活性。初步数据显示，在实验性肺动脉高压中，使用89Zr-贝伐单抗的PET成像检测到肺血管远端循环中血管内皮生长因子的活性增强，并有可能识别人肺动脉高压中的活动性重塑病变。这些研究将直接测试PET 89Zr-贝伐单抗成像是否可以在发生重大血管丢失和血流动力学显著的PAH之前发现早期疾病，预测疾病的严重程度和进展，并反映经批准的血管扩张剂和新的治疗干预措施拦截肺循环中血管新生重塑活动的能力。验证研究将使用受PAH影响的活体、移植的人肺进行，使用体外灌流方法，以提高对这些发现的可译性的信心。这种方法的验证将是我们评估临床医生通常无法接触到的血管床中正在进行的重塑的能力的突破，允许对疾病严重程度和风险进行客观分层，根据疾病活动量身定做药物治疗，并有可能确定通过全新机制作用的治疗方法来阻止或逆转疾病进展。(摘要结束)