Mechanisms of defective mitophagy and cellular senescence in HIV associated COPD

项目摘要 在老龄化的艾滋病毒感染人群中，共病是发病率和死亡率的重要决定因素。 肺部疾病，如细菌性肺炎、慢性阻塞性肺病和肺动脉高压正在成为重要的 艾滋病毒感染者的合并症COPD仍然是HIV感染者的重要合并症， 尽管抗逆转录病毒治疗成功地恢复了CD 4细胞计数， 肺囊虫感染。HIV是COPD的一个独立危险因素，即使在吸烟补偿时也是如此 status.衰老相关的促炎细胞因子在慢性炎症中起重要作用 这是慢性阻塞性肺疾病的标志。受损的线粒体自噬导致去极化缺陷线粒体的积累 这表明ROS的产生和损伤相关分子模式（DAMP）的释放增加 伴随着衰老相关分泌表型（SASP）相关细胞因子的增加。 吸烟是艾滋病毒感染者尼古丁成瘾的主要途径。药理 尼古丁介导的多巴胺、谷氨酸和GABA释放的作用引起尼古丁依赖。一 艾滋病毒感染者中有相当多的人对尼古丁和烟草上瘾， 在美国的普通民众中。我们发现，艾滋病毒达特和香烟烟雾介导的一些 它们通过涉及TGF-β信号传导的共同途径发挥作用。达特和TGF-β改变了 支气管上皮细胞导致抑制一些关键基因参与线粒体自噬和一般 大自噬结合我们的报告，艾滋病毒达特和吸烟增加肺 这表明改变的microRNAome可能表现为HIV和CS中的起始事件， 在HIV吸烟者中观察到COPD与发病严重程度增加相关。因此中和了艾滋病毒达特， 调节气道中的TGF-β信号传导可以阻止或甚至逆转肺“炎症”，从而预防或 减缓临床疾病的发生。 基于这些观察，Aim 1将确定参与HIV达特和香烟的miRNA的作用 与吸烟相关的线粒体自噬受损。目的2将涉及改变线粒体自噬和随之而来的衰老， 原代小气道上皮细胞（SAEC）中SASP相关细胞因子和DAMP的分泌增加 体外和小动物肺特异性达特转基因模型和来自HIV供体肺 吸烟者/不吸烟者。目的3将确定挽救达特和TGF-β对肿瘤细胞增殖的作用的治疗方法。 挽救线粒体自噬并因此抑制应激诱导的衰老和异常SASP细胞因子， 阻尼器。该提案旨在解决艾滋病毒研究的一个主要优先领域 即艾滋病毒感染者和药物滥用者的共病。

PROJECT SUMMARY In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Lung diseases such as bacterial pneumonia, COPD and pulmonary hypertension are emerging as significant comorbidities in the people living with HIV. COPD continues to be an important comorbidity in HIV- infected patients even though anti-retroviral therapy has succeeded in restoring CD4 cell counts and decreasing infections by pneumocystis. HIV is an independent risk factor for COPD even when compensated for smoking status. Senescence associated proinflammatory cytokines play and important role in the chronic inflammation which is a hallmark of COPD. Impaired mitophagy leads to accumulation of depolarized defective mitochondria that demonstrates increased ROS production and release of Damage associated Molecular patterns (DAMPs) with a concomitant increase in senescence associated secretory phenotype (SASP) associated cytokines. Cigarette smoking is the primary means of nicotine addiction in people living with HIV. The pharmacologic effects of nicotine-mediated release of dopamine, glutamate and GABA cause nicotine dependence. A disproportionately high number of HIV infected people are addicted to nicotine and smoke tobacco compared to the general population in the United States. We show that HIV Tat and cigarette smoke mediate some of their effects via a common pathway involving TGF-β signaling. Tat and TGF-β alter the microRNAome of bronchial epithelial cells leading to suppression of some of the key genes involved in mitophagy and general macroautophagy. Taken together with our reports that HIV Tat and Cigarette smoke increase lung inflammation, this suggests that the altered microRNAome may manifest as the initiating event in HIV and CS associated COPD with increased severity of onset observed in HIV smokers. Hence neutralizing HIV tat and modulating TGF-β signaling in the airway can arrest or even reverse lung “inflammaging” thereby preventing or slowing down the onset of clinical disease. Based on these observations, Aim 1 will determine the role of miRNAs involved in HIV Tat and cigarette smoke associated impaired mitophagy. Aim 2 will relate altered mitophagy and consequent senescence with increased secretion in SASP associated cytokines and DAMPs in primary small airway epithelial cells (SAECs) in vitro and in small animal lung-specific Tat transgenic models and donor lungs from HIV smokers/nonsmokers. Aim 3 will determine therapeutic approaches to rescue the effects of Tat and TGF-β to rescue mitophagy and consequently inhibit stress induced senescence and aberrant SASP cytokines and DAMPs. The proposal aims will address one of the major high priority areas identified for HIV research namely comorbidities in people living with HIV and substance abuse.