Caveolin-1-mediated senescence, chronic inflammation and age-related lung disease

Caveolin-1介导的衰老、慢性炎症和年龄相关性肺部疾病

基本信息

批准号：
9279206
负责人：
FERRUCCIO GALBIATI
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279206
关键词：
Acute Animals Autophagocytosis Binding Biological Process CXCR3 gene Cell Cycle Arrest Cells Chronic Complex Conditioned Culture Media Data Development Disease Experimental Designs Exposure to Fibroblasts Future Genes In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Investigation Knockout Mice Link Lung Lung Inflammation Lung diseases Macrophage Colony-Stimulating Factor Mediating Metabolic Molecular Mus NF-kappa B Nitric Oxide Pathogenesis Patients Peptide Hydrolases Play Protease Inhibitor Proteins Publishing Pulmonary Emphysema RANTES Research Proposals Role Scaffolding Protein Signal Transduction Signaling Molecule Small Interfering RNA Smoke Source TP53 gene Testing Up-Regulation age related beneficiary caveolin 1 cigarette smoke-induced cigarette smoking cigarette smoking cytokine environmental tobacco smoke exposure in vivo inhibition of autophagy insight macrophage mutant novel novel therapeutic intervention prevent public health relevance response senescence

Acute Animals Autophagocytosis Binding Biological Process CXCR3 gene Cell Cycle Arrest Cells Chronic Complex Conditioned Culture Media Data Development Disease Experimental Designs Exposure to Fibroblasts Future Genes In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Investigation Knockout Mice Link Lung Lung Inflammation Lung diseases Macrophage Colony-Stimulating Factor Mediating Metabolic Molecular Mus NF-kappa B Nitric Oxide Pathogenesis Patients Peptide Hydrolases Play Protease Inhibitor Proteins Publishing Pulmonary Emphysema RANTES Research Proposals Role Scaffolding Protein Signal Transduction Signaling Molecule Small Interfering RNA Smoke Source TP53 gene Testing Up-Regulation age related beneficiary caveolin 1 cigarette smoke-induced cigarette smoking cigarette smoking cytokine environmental tobacco smoke exposure in vivo inhibition of autophagy insight macrophage mutant novel novel therapeutic intervention prevent public health relevance response senescence

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项目摘要

DESCRIPTION (provided by applicant): Emphysema is an age-related and chronic inflammatory disease that is largely associated with exposure to cigarette smoke and is caused by a protease/antiprotease imbalance in the lungs. The identification of the cellular origin of the inflammatory mediators and the mechanisms underlying their expression and function is fundamental for gaining insight into the link between chronic inflammation and age-related lung disease. Senescent cells are characterized by irreversible cell cycle arrest. They remain metabolically active and are capable of secreting mediators of inflammation in vitro. Chronic exposure to cigarette smoke induces senescence of lung fibroblasts in mice, and hallmarks of senescence are found in lung fibroblasts of emphysema patients. Interestingly, our published data show that caveolin-1 promotes chronic cigarette smoke-induced senescence of lung fibroblasts in mice. To determine whether a causal relationship exists between caveolin-1-mediated senescence of lung fibroblasts and development of emphysema, we propose to test the novel paradigm that caveolin-1-mediated inhibition of autophagy promotes smoke-induced autophagy-to-senescence transition (AST) of lung fibroblasts, which become a chronic source of pro-inflammatory cytokines that stimulate the release of proteases by inflammatory cells, therefore contributing to the development of pulmonary emphysema. This central hypothesis will be tested by pursuing three specific aims: Aim 1: Determine the molecular mechanism of autophagy-to-senescence transition in lung fibroblasts. Hypothesis: caveolin-1 is a novel beclin-1-interacting protein. Caveolin-1 promotes cigarette smoke-induced AST of lung fibroblasts by inhibiting autophagy through disruption of the beclin-1/Vps34 complex. Aim 2: Identify the molecular mechanism and functional significance of the cigarette smoke-induced and caveolin-1-mediated chronic release of mediators of inflammation by senescent fibroblasts. Hypothesis: caveolin-1, through inhibition of eNOS activity, promotes the NF-kB-mediated sustained expression and secretion of cytokines by senescent fibroblasts that underwent AST, which stimulate the release of proteases by inflammatory cells. Aim 3: Determine if caveolin-1-mediated senescence of lung fibroblasts promotes chronic lung inflammation and emphysema in vivo. Hypothesis: chronic exposure to cigarette smoke induces senescence of lung fibroblasts, which promote chronic lung inflammation and contribute to the pathogenesis of emphysema in a caveolin-1-dependent fashion in vivo. These investigations will identify the caveolin-1-mediated switch from autophagic to senescent signaling as a novel biological process that is relevant to chronic lung inflammation and the pathogenesis of emphysema. Novel cellular and molecular mechanisms will be determined that have the potential to directly impact the future development of novel therapeutic interventions for the treatment of age-related lung disease.

描述（由适用提供）：肺气肿是一种与年龄相关的慢性炎症性疾病，主要与暴露于香烟烟雾有关，是由肺部蛋白酶/抗蛋白酶失衡引起的。鉴定细胞来源炎症介质以及其表达和功能的基础机制对于洞悉慢性炎症与与年龄相关的肺部疾病之间的联系至关重要。衰老细胞的特征是不可逆的细胞周期停滞。它们保持代谢活跃，能够在体外分泌炎症介质。长期暴露于香烟烟雾会引起小鼠肺成纤维细胞的感受，并且在肺气肿患者的肺成纤维细胞中发现了感应标志。有趣的是，我们发表的数据表明，小鼠1促进了小鼠肺成纤维细胞的慢性烟雾诱导的感应。为了确定小窝蛋白1介导的肺成纤维细胞的敏感和肺气肿的发展，我们建议测试新的范式，即小窝蛋白1介导的自噬抑制抑制烟雾引起的烟雾诱导的自噬 - 渗透到味道过渡（AST），通过肺成纤维细胞的释放，这是一个繁殖的刺激，这是一个繁殖的刺激，这是一个模仿刺激的刺激性，这是一个繁殖的刺激性的，这是一个繁殖的刺激性的刺激性，该刺激的刺激性刺激了刺激性的刺激性。细胞，因此有助于肺肺气肿的发展。该中心假设将通过追求三个特定目的来检验：目标1：确定肺成纤维细胞中自噬至味道转变的分子机制。假设：小窝蛋白-1是一种新型的Beclin-1相互作用蛋白。 Caveolin-1通过破坏Beclin-1/VPS34复合物来抑制自噬，从而促进肺成纤维细胞的烟雾引起的AST。 AIM 2：确定香烟烟雾诱导的和小窝蛋白-1介导的慢性炎症介体炎症的慢性释放的分子机制和功能意义。假设：小窝蛋白1通过抑制eNOS活性，促进了通过经历AST的感觉成纤维细胞对NF-KB介导的持续表达和细胞因子分泌，从而刺激炎性细胞释放蛋白酶。 AIM 3：确定小窝蛋白-1介导的肺成纤维细胞的感应是否促进了慢性肺部感染和体内肺气肿。假设：长期暴露于香烟烟雾会诱导肺成纤维细胞的感应，从而促进慢性肺部感染并在体内依赖caveolin-1依赖性时尚肺气肿的发病机理。这些研究将确定可爱素1介导的从自噬到感觉信号传导的切换，是一种与慢性肺部感染和肺气肿的发病机理有关的新生物学过程。将确定新型的细胞和分子机制，这些机制具有直接影响新型治疗干预措施以治疗与年龄相关的肺部疾病的未来发展。