In vivo imaging of destructive processes in COPD

 描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是第三大死亡原因，其特征在于临床症状和肺量测定。可以使用CT等成像方式采取其他诊断措施。然而，由于成像方式只能评估终末器官损伤，因此无法可视化病理过程的激活，从而限制了COPD中肺破坏的评估。在这个提议中，我们的目标是开发分子成像探针，以靶向COPD的启动和进展中的两个关键过程。细胞凋亡是一种程序性细胞死亡过程，与COPD严重程度相关，在正常成人肺或无COPD的吸烟者肺中未见。在过去的几年中，我们已经证明了AxV-128/99mTc在兔烟雾暴露肺气肿模型中体内检测细胞凋亡的成功能力。此外，1期研究已经证明了这种药物在健康患者中的安全性。因此，在本提案的前两个目标中，我们将为临床带来AxV-128/99mTc，一种膜联蛋白V靶向SPECT/CT成像探针，用于对COPD患者的疾病进行成像。在第一个目标中，我们将确定AxV-128/99mTc的使用是否允许COPD患者的细胞凋亡成像。在第二个目标中，我们将确定AxV-128/99mTc SPECT-CT成像是否识别COPD患者与非COPD个体相比的围手术期肺损伤。第三个目标是开发一种新的基质金属蛋白酶（MMP）靶向显像剂。虽然细胞凋亡是COPD发病机制的重要组成部分，但MMP的产生是肺破坏过程的基础。因此，在这个最终的目标，我们将进行临床前研究与MMP探针，以检测MMP在体内的存在。我们的假设是，MMP探针的开发将补充COPD患者人群中细胞凋亡的成像。如果成功，这种方法将成为一种强大的工具，可以预测诊断后的疾病进展，识别疾病加重相关肺功能下降的风险患者，并监测对疾病靶向治疗的反应。(End摘要）

 DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is characterized by clinical symptoms and spirometry. Additional measures for diagnosis can be taken using imaging modalities such as CT. However, the evaluation of lung destruction in COPD is limited by the inability to visualize the activation f pathological processes since imaging modalities are only able to evaluate end-organ damage. In this proposal, we aim to develop molecular imaging probes to target two critical processes in the initiation and progression of COPD. Apoptosis, a process of programmed cellular death, correlates with COPD severity and is not seen in the normal adult lung or in the lungs of smokers without COPD. In the past several years we have demonstrated the successful ability of AxV-128/99mTc to detect apoptosis in vivo in a rabbit smoke exposure emphysema model. Additionally, Phase 1 studies have demonstrated safety of this agent in healthy patients. Therefore, in the first two aims of this proposal we will bring to the clinic AxV-128/99mTc, an Annexin V targeted SPECT/CT imaging probe, to image disease in patients with COPD. In the first Aim we will determine whether the use of AxV-128/99mTc allows the imaging of apoptosis in patients with COPD. In the second Aim we will determine if AxV-128/99mTc SPECT-CT imaging identifies peri-operative lung injury in patients with COPD compared to individuals without COPD. In a third aim, we will develop a new matrix metalloproteinase (MMP) targeted imaging agent. Although apoptosis is an important component of COPD pathogenesis, MMP production is fundamental to the process of lung destruction. Therefore, in this final aim we will perform preclinical studies with an MMP probe in order to detect the presence of MMPs in vivo. It is our hypothesis that the development an MMP probe would complement imaging of apoptosis in a COPD patient population. If successful, such an approach will be a powerful tool to potentially predict disease progression after diagnosis, identify patients at risk for disease exacerbation related lung function decline, and monitor response to disease targeted therapy. (End of Abstract)