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

• 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
• 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

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）：肺部疾病的成像模式侧重于评价末端损伤和破坏。对与疾病发病机制相关的细胞过程和靶点进行成像的方法的发展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，暴露于烟草烟雾导致炎症、空气空间扩大、肺泡破坏、肺泡血管损失和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受体（RECEPTOR for Advanced Glycation End-products，RECEPTOR）的信号传导刺激炎症通路，该受体结合许多激活细胞内通路的配体，导致炎性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肺促炎信号传导和SPECT成像的细胞凋亡来证明肺部炎症。本研究将有助于我们更好地理解细胞凋亡和凋亡在肺气肿发病机制中的作用。在目标1中，我们将开发和验证一种成像方法，该方法针对烟雾暴露小鼠的神经活动。在目标2中，我们将在暴露于香烟烟雾的肺气肿兔模型中成像细胞凋亡。在目标3中，我们将评估兔肺气肿模型中炎症和凋亡的时间过程，将炎症和凋亡活性的峰值水平与结构变化相关联。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治疗的替代标志物。