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

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

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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）是一种肺血管耐药性升高的疾病，其特征是肺循环的耐药性降解和消除抗药性。尽管目前的疗法，但诊断为PAH后的生存仍在5年时仍约50％，这是由于疾病进展和心力衰竭而导致的死亡率。延迟的诊断，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PAH改善结果的障碍。直接监测肺血管疾病活性的敏感，无创成像测试，可以帮助加快诊断并确定有效的干预措施。该建议将使用89zR-Bevacizumab验证新型正电子发射断层扫描（PET）分子成像方式的实用性，以检测受pH影响的血管中的病理VEGF活性。初步数据表明，使用89ZR-贝伐单抗的PET成像检测到实验性PAH中肺脉管系统的静态循环中的VEGF活性增强，并且有可能识别人类PAH中重塑的主动病变。这些研究将直接测试PET 89ZR-贝伐单抗成像是否可以检测早期疾病，在发生明显的血管丧失和血流动力学意义上的PAH之前，预测疾病的严重程度和进展，并反映了认可的血管疾病和新颖的治疗性干预措施，以拦截血管生成性重透明活性。验证研究将使用活体灌注方法的生活，受PAH影响的人类肺部进行，以提高对这些发现的转换性的信心。这种方法的验证将构成我们评估临床医生通常无法接近的血管床中正在进行的重塑的能力的突破，以允许对疾病严重程度和RIK的客观分层，基于疾病活动的量身定制药物治疗，并有可能通过抑制或反向疾病进展的新型机制来识别疗法。（抽象的结尾）