Imaging RAGE Pro-inflammatory Signaling and Cellular Apoptosis in Emphysema

描述（由申请人提供）：肺部疾病的成像模式侧重于评估末端损伤和破坏。与疾病发病机制相关的细胞过程和靶点成像方法的发展可能允许对疾病的时间过程进行评估并提供预后信息。在肺气肿中，暴露于烟草烟雾会导致炎症、空气空间扩大、肺泡破坏、肺泡血管丧失和最终不可逆转的肺破坏。研究表明，香烟烟雾可以通过晚期糖基化终产物受体（RAGE）发出信号，刺激炎症通路，RAGE结合许多激活细胞内通路的配体，导致炎症细胞因子的释放和与细胞凋亡相关的通路。通过本提案中描述的研究，我们试图通过定量香烟烟雾诱导的RAGE促炎信号和SPECT成像的细胞凋亡来证明肺部炎症。本文提出的研究将提高我们对RAGE和细胞凋亡在肺气肿发病机制中的作用的理解。在目标1中，我们将开发并验证一种针对烟雾暴露小鼠中RAGE活性的成像方法。在目的2中，我们将在暴露于香烟烟雾的家兔肺气肿模型中成像细胞凋亡。在Aim 3中，我们将评估兔肺气肿模型的炎症和细胞凋亡的时间过程，将RAGE峰值水平和细胞凋亡活性与结构变化联系起来。我们还将确定戒烟对这些信号的影响。在相关动物模型中开发这些成像工具有可能识别和量化早期肺损伤，预测结果，并作为评估戒烟和其他治疗的替代标记物。

DESCRIPTION (provided by applicant): Imaging modalities in lung disease focus on the evaluation of end damage and destruction. The development of methods to image cellular processes and targets related to disease pathogenesis may allow evaluation over the time course of disease and provide prognostic information. In emphysema, exposure to tobacco smoke leads to inflammation, airspace enlargement, lung alveolar destruction, loss of alveolar blood vessels and eventual irreversible lung destruction. Studies have shown that cigarette smoke can stimulate inflammatory pathways by signaling through the receptor for advanced glycation end-products (RAGE), which binds a number of ligands that activate intracellular pathways, leading to release of inflammatory cytokines and to pathways linked to apoptosis. Through the studies described in this proposal, we seek to demonstrate lung inflammation through the quantification of cigarette smoke induced RAGE pro-inflammatory signaling and cellular apoptosis with SPECT imaging. The studies presented in this proposal will improve our understanding of the role of RAGE and apoptosis in emphysema pathogenesis. In Aim 1, we will develop and validate an imaging methodology that targets RAGE activity in the smoke exposed mouse. In Aim 2, we will image apoptosis in a cigarette smoke exposed rabbit model of emphysema. In Aim 3, we will evaluate the time course of inflammation and apoptosis in the rabbit model of emphysema, correlating peak levels of RAGE and apoptosis activity with structural changes. We will also determine the effect of smoking cessation on these signals. The development of these imaging tools in relevant animal models has the potential to identify and quantify early lung damage, predict outcome and serve as a surrogate marker to assess smoking cessation and other therapies.