Imaging RAGE Pro-inflammatory Signaling and Cellular Apoptosis in Emphysema

肺气肿中 RAGE 促炎信号传导和细胞凋亡的成像

基本信息

批准号：
8550823
负责人：
Jeanine M D'Armiento
金额：
$ 37.39万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550823
关键词：
Advanced Glycosylation End Products Alveolar Animal Model Animals Antibodies Apoptosis Apoptotic Binding Blood Vessels Cell physiology Chronic Obstructive Airway Disease Development Disease Disease Progression Evaluation Exposure to Functional Imaging Image Imaging Device Imaging Techniques Immunohistochemistry Inflammation Inflammatory Knockout Mice Laboratories Life Ligands Link Lung Lung Inflammation Lung diseases Mammalian Cell Measurement Methodology Modeling Monitor Monocrotaline Mus Oryctolagus cuniculus Outcome Pathogenesis Pathway interactions Patients Physiological Pulmonary Emphysema Pulmonary Pathology Radiolabeled Rage Rattus Role Series Signal Pathway Signal Transduction Smoke Specificity Surrogate Markers Time Tobacco smoke Validation abstracting alveolar destruction annexin A5 cellular targeting cigarette smoke-induced cigarette smoking cinnamycin cytokine imaging modality improved in vivo method development molecular imaging novel prognostic radiotracer receptor research study single photon emission computed tomography smoking cessation uptake

项目摘要

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.

描述（由申请人提供）：肺部疾病的成像方式侧重于评估末端损伤和破坏。开发与疾病发病机制相关的细胞过程和靶标成像方法可以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，接触烟草烟雾会导致炎症、气腔扩大、肺泡破坏、肺泡血管损失以及最终不可逆的肺破坏。研究表明，香烟烟雾可以通过晚期糖基化终产物 (RAGE) 受体发出信号来刺激炎症通路，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 SPECT 成像量化香烟烟雾诱导的 RAGE 促炎症信号传导和细胞凋亡来证明肺部炎症。本提案中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暴露于烟雾的小鼠的 RAGE 活动的成像方法。在目标 2 中，我们将对暴露于香烟烟雾的兔肺气肿模型中的细胞凋亡进行成像。在目标 3 中，我们将评估兔肺气肿模型中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相关联。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疗法的替代标记。