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

基本信息

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
项目类别：
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

项目摘要

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，尽管采用了目前的治疗方法，但诊断出 PAH 后的 5 年生存率仍约为 50%，且死亡率较高。疾病进展和右心衰竭的延迟诊断、缺乏更直接的疾病活动生物标志物以及缺乏可以阻止或逆转肺血管重塑的治疗方法都是改善 PAH 预后的障碍。直接监测肺血管疾病活动的敏感、非侵入性成像测试可以帮助加快诊断并确定有效的干预措施，该提案将验证一种新型正电子发射断层扫描 (PET) 分子成像模式的实用性，即使用 89Zr-贝伐珠单抗来检测病理。受 PH 影响的血管中的 VEGF 活性表明，使用 89Zr-贝伐单抗的 PET 成像可检测到肺远端循环中 VEGF 活性的增强。这些研究将直接测试 PET 89Zr-贝伐单抗成像是否可以在显着血管损失和血流动力学显着的 PAH 发生之前检测到早期疾病。预测疾病的严重程度和进展，并反映已批准的血管扩张剂和新型治疗干预措施拦截肺循环中血管生成重塑活动的能力。验证研究将使用活体移植人体进行。使用离体灌注方法对受 PAH 影响的肺部进行研究，以提高对这些发现的可转化性的信心，该方法的验证将构成我们评估通常无法支持的血管床正在进行的重塑能力的突破。允许对疾病严重程度和风险进行客观分层，根据疾病活动度调整药物治疗，并可能确定通过全新机制发挥作用的疗法来阻止或逆转疾病进展（摘要结束）。