Ceramide-induced lung destruction in emphysema

肺气肿中神经酰胺引起的肺破坏

基本信息

批准号：
7645005
负责人：
Irina Petrache
金额：
$ 26.93万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7645005
关键词：
1,2-diacylglycerol Abbreviations Alveolar Alveolar Cell Alveolar wall Animal Experiments Animal Model Apoptosis Apoptotic Arts Atherosclerosis Biological Assay Blood capillaries Cell Culture Techniques Cells Ceramides Cessation of life Chronic Complement Data Development Diglycerides Disease Distal Employee Strikes Endothelial Cells Epithelial Cells Equilibrium Event Fatty Acids Feedback Fumonisins Generations High Pressure Liquid Chromatography Human Immunohistochemistry Injury Investigation Kinetics Link Liquid Chromatography Lung Lung Inflammation Lung diseases Macrophage Activation Maintenance Mass Spectrum Analysis Measurement Mediating Mediator of activation protein Medicine Modeling Molecular Mus Names Nature Organ Oxidative Stress Pathogenesis Pathway interactions Patients Peptide Hydrolases Phenotype Play Positioning Attribute Prevention Process Production Protease Inhibitor Proteolysis Publications Pulmonary Emphysema RNA Interference Radiation Rattus Reactive Oxygen Species Receptor Inhibition Regulation Reporting Research Personnel Role Serine Signal Transduction Smoking Sphingolipids Sphingomyelinase Sphingosine Structure of parenchyma of lung Terminal Bronchiole Tissues Transferase Up-Regulation Vascular Endothelial Growth Factor Receptor Work acid sphingomyelinase alveolar destruction capillary cigarette smoking cigarette smoking dihydroceramide effective therapy human subject inhibitor/antagonist inorganic phosphate liquid chromatography mass spectroscopy novel paracrine prevent programs repaired restoration thermozymocidin

项目摘要

DESCRIPTION (provided by applicant): Pulmonary emphysema is a prevalent lung disease with no effective treatment. Its unique features are the ultimate disappearance of lung tissue and loss of alveoler-capillary units. The lung destruction becomes sustained and progressive even long after discontinuation of smoking. Only recently, investigations (e.g., via inhibition of vascular endothelial growth factor receptor, VEGFR-inh) have uncovered a critical role for apoptosis in emphysema pathogenesis, in conjunction with oxidative stress and matrix protease activation, all of which synergize, triggering alveolar destruction. Key to developing treatments for emphysema patients is identifying the molecular mechanisms that trigger, amplify, and sustain alveolar cell destruction. Ceramide, a signaling sphingolipid, is now known to be a critical mediator of apoptosis in different organs. We recently demonstrated that ceramide is a key mediator of lung apoptosis and emphysema in the established VEGFR- inh model of emphysema in both mice and rats. Moreover, we developed cutting-edge approaches to quantify ceramide and its fatty acid profile and report striking increases in its different molecular species in the lungs of emphysema patients. Together with evidence linking ceramide with oxidative stress and protease induction, these data firmly position ceramide as a novel and potentially key mediator of multiple processes linked to emphysema pathogenesis. Therefore, we hypothesize that an imbalanced, upregulated ceramide signaling triggers mechanisms that cause and amplify the alveolar destruction in emphysema. These mechanisms, hereby named "destructive pathways", involve lung cell apoptosis, oxidative stress, and matrix proteolysis. In Specific Aim (SA) #1 we will investigate whether ceramide upregulation is necessary and sufficient to trigger emphysema. We will utilize the VEGFR-inh model and inhibit ceramide by pharmacologic, and molecular (acid sphingomyelinase and serine-palmitoyl transferase SiRNA) strategies. In SA #2 we will identify the mechanisms by which ceramide self-amplifies its synthesis, thereby triggering a further, paracrine level of amplification of alveolar destruction. Finally, SA #3 will propose that restoring the balance of sphingolipid signaling of the pro-apoptotic ceramide vs. pro-survival sphingosine-1-P will block alveolar apoptosis and thus emphysema. Once understood, the molecular dis-regulation of ceramide could offer a target for treatments and/or prevention of emphysema.

描述（由申请人提供）：肺肺气肿是一种普遍的肺部疾病，没有有效治疗。它的独特特征是肺组织的最终消失和肺泡毛细血管单元的丧失。甚至在停止吸烟后很长时间，肺部破坏就会持续和渐进。直到最近，研究（例如，通过抑制血管内皮生长因子受体，VEGFR-INH）的研究才发现了凋亡在肺气肿发病机理中的关键作用，并结合氧化应激和基质蛋白酶激活，所有这些都协同，触发了巨大的破坏性破坏。开发肺气肿患者治疗方法的关键是确定触发，扩增和维持肺泡细胞破坏的分子机制。神经酰胺是一种信号鞘脂，现在已知是不同器官凋亡的关键介体。我们最近证明，神经酰胺是在小鼠和大鼠中已建立的VEGFR- INH模型中肺凋亡和肺气肿的关键介体。此外，我们开发了量化神经酰胺及其脂肪酸概况的尖端方法，并报告了其在肺气肿患者肺中不同分子物种的惊人幅度增加。以及将神经酰胺与氧化应激和蛋白酶诱导联系起来的证据，这些数据将神经酰胺牢固地定位为与肺气肿发病机理相关的多种过程的新型和潜在的关键介体。因此，我们假设一种不平衡，上调的神经酰胺信号传导触发并扩大了肺气肿的肺泡破坏的机制。这些机制被称为“破坏性途径”，涉及肺细胞凋亡，氧化应激和基质蛋白水解。在特定的目标（SA）＃1中，我们将研究神经酰胺的上调是否需要且足以触发肺气肿。我们将利用VEGFR-INH模型，并通过药理学和分子（酸鞘磷脂酶和丝氨酸 - 甲虫转移酶siRNA）抑制神经酰胺。在SA＃2中，我们将确定神经酰胺会自我放大其合成的机制，从而触发进一步的旁分泌肺泡破坏的旁分泌水平。最后，SA＃3将提出，恢复促凋亡神经酰胺与促生物存在的鞘氨酸-1-P的鞘脂信号的平衡将阻止肺泡凋亡，从而阻止肺气肿。一旦理解，神经酰胺的分子分解就可以为治疗和/或预防肺气肿提供一个靶标。