In vivo imaging of destructive processes in COPD

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)是第三大死亡原因，以临床症状和肺活量测定为特征。可以使用CT等成像手段来采取其他诊断措施。然而，由于成像手段只能评估终末器官损害，因此无法可视化病理过程的激活，从而限制了对COPD患者肺损害的评估。在这项建议中，我们的目标是开发分子成像探针，以靶向COPD发生和发展的两个关键过程。细胞凋亡是一种程序性细胞死亡过程，与COPD的严重程度相关，在正常成人肺或非COPD吸烟者的肺中未见。在过去的几年里，我们已经成功地证明了AxV-128/99mTc能够在体内检测烟雾暴露的兔肺气肿模型中的细胞凋亡。此外，1期研究已经证明该制剂在健康患者中是安全的。因此，在这项提案的前两个目标中，我们将把一种针对Annexin V的SPECT/CT成像探针AxV-128/99mTc带到临床上，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的使用是否允许对COPD患者的细胞凋亡进行成像。在第二个目标中，我们将确定与非COPD患者相比，AxV-128/99mTcSPECT-CT成像是否能够识别COPD患者围手术期肺损伤。在第三个目标中，我们将开发一种新的基质金属蛋白酶(MMP)靶向显像剂。尽管细胞凋亡是COPD发病机制中的一个重要组成部分，但基质金属蛋白酶的产生是肺破坏过程中的基础。因此，在这个最终目标中，我们将使用基质金属蛋白酶探针进行临床前研究，以检测体内基质金属蛋白酶的存在。我们的假设是，开发一种基质金属蛋白酶探针将补充COPD患者群体中细胞凋亡的成像。如果成功，这种方法将成为一种强大的工具，可以潜在地预测诊断后的疾病进展，识别与肺功能下降相关的疾病恶化风险，并监测对疾病靶向治疗的反应。(摘要结束)

 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)