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：
8903586
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：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903586
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 Health IL6 gene In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Investigation Knockout Mice Link Lung Lung Inflammation Lung diseases Macrophage Colony-Stimulating Factor Mediating 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 Smoke Source Testing Up-Regulation age related beneficiary caveolin 1 chemokine cigarette smoke-induced cigarette smoking cigarette smoking in vivo inhibition of autophagy insight macrophage mutant novel novel therapeutic intervention prevent response senescence

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 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 fibroblasts 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 chemokines 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 chemokines 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（由申请人提供）：肺气肿是一种与年龄相关的慢性炎症性疾病，很大程度上与接触香烟烟雾有关，并由肺部蛋白酶/抗蛋白酶失衡引起。识别炎症介质的细胞起源及其表达和功能的机制对于深入了解慢性炎症与年龄相关性肺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。它们保持代谢活性并能够在体外分泌炎症介质。长期接触香烟烟雾会导致成纤维细胞衰老，并且在肺气肿患者的肺成纤维细胞中发现了衰老特征。有趣的是，我们发表的数据表明，caveolin-1 会促进慢性香烟烟雾引起的小鼠肺成纤维细胞的衰老。为了确定caveolin-1介导的肺成纤维细胞衰老与肺气肿的发展之间是否存在因果关系，我们建议测试caveolin-1介导的自噬抑制促进烟雾诱导的自噬向衰老转变的新范式（AST ）肺成纤维细胞，成为促炎趋化因子的长期来源，刺激炎症细胞释放蛋白酶，从而导致肺气肿的发展。这一中心假设将通过追求三个具体目标来检验：目标 1：确定肺成纤维细胞自噬到衰老转变的分子机制。假设：caveolin-1 是一种新型 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，从而促进香烟烟雾诱导的肺成纤维细胞的 AST。目标 2：确定香烟烟雾诱导和 Caveolin-1 介导的衰老成纤维细胞慢性释放炎症介质的分子机制和功能意义。假设：caveolin-1通过抑制eNOS活性，促进经历AST的衰老成纤维细胞介导的NF-kB介导的趋化因子的持续表达和分泌，从而刺激炎症细胞释放蛋白酶。目标 3：确定 Caveolin-1 介导的肺成纤维细胞衰老是否会促进体内慢性肺部炎症和肺气肿。假设：长期接触香烟烟雾会诱导肺成纤维细胞衰老，从而促进慢性肺部炎症，并以 Caveolin-1 依赖性方式导致体内肺气肿的发病机制。这些研究将确定 Caveolin-1 介导的从自噬信号到衰老信号的转变是一种与慢性肺部炎症和肺气肿发病机制相关的新生物过程。将确定新的细胞和分子机制，这些机制有可能直接影响治疗与年龄相关的肺部疾病的新型治疗干预措施的未来发展。