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

 描述(申请人提供)：肺气肿是一种与年龄相关的慢性炎症性疾病，主要与吸烟有关，由肺部的蛋白酶/抗蛋白酶失衡引起。细菌细胞起源的鉴定 炎症介质及其表达和功能的潜在机制是深入了解慢性炎症和年龄相关性肺部疾病之间联系的基础。衰老细胞的特征是不可逆的细胞周期停滞。它们在体外保持新陈代谢活性，并能够分泌炎症介质。长期暴露在香烟烟雾中会导致小鼠肺成纤维细胞衰老，肺气肿患者的肺成纤维细胞也有衰老的特征。有趣的是，我们发表的数据表明，小窝蛋白-1促进了慢性香烟烟雾诱导的小鼠肺成纤维细胞的衰老。为了确定小窝蛋白-1介导的肺成纤维细胞衰老与肺气肿的发生之间是否存在因果关系，我们建议测试小窝蛋白-1介导的抑制自噬促进烟雾诱导的肺成纤维细胞自噬向衰老转变(AST)的新范式，肺成纤维细胞成为促炎细胞因子的慢性来源，刺激炎症细胞释放蛋白酶，从而促进肺气肿的发生。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向衰老转变的分子机制。假设：Caveolin-1是一种新的Beclin-1相互作用蛋白。小窝蛋白-1通过破坏Beclin-1/Vps34复合体来抑制自噬，从而促进香烟烟雾诱导的肺成纤维细胞的AST。目的：探讨香烟烟雾和小窝蛋白-1介导的衰老成纤维细胞慢性释放炎症介质的分子机制及其功能意义。假设：Caveolin-1通过抑制eNOS活性，促进经AST治疗的衰老成纤维细胞持续表达和分泌细胞因子，从而刺激炎症细胞释放蛋白酶。目的：在体内研究小窝蛋白-1介导的肺成纤维细胞衰老是否促进慢性肺炎症和肺气肿。假设：长期暴露在香烟烟雾中会导致肺成纤维细胞衰老，从而促进慢性肺部炎症，并在体内以小窝蛋白-1依赖的方式参与肺气肿的发病。这些研究将确认小窝蛋白-1介导的从自噬信号到衰老信号的转换是一种新的生物学过程，与慢性肺部炎症和肺气肿的发病机制有关。新的细胞和分子机制将被确定，这些机制有可能直接影响治疗年龄相关肺部疾病的新的治疗干预措施的未来发展。

 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.