Mechanisms of defective mitophagy and cellular senescence in HIV associated COPD

项目总结 在老年艾滋病毒感染人群中，并存疾病是发病率和死亡率的重要决定因素。 细菌性肺炎、慢性阻塞性肺病和肺动脉高压等肺部疾病正在成为重要的 艾滋病毒携带者的合并症。慢性阻塞性肺病仍然是艾滋病毒感染者的一种重要的共病 患者即使抗逆转录病毒治疗已经成功地恢复了CD4细胞计数并降低了 肺孢子虫感染。艾滋病毒是COPD的独立危险因素，即使在吸烟的补偿下也是如此 状态。衰老相关促炎细胞因子在慢性炎症中的作用 这是慢性阻塞性肺病的一个特征。吞噬丝裂功能受损导致去极化缺陷线粒体积累 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。 吸烟是艾滋病毒携带者尼古丁成瘾的主要方式。药理学 尼古丁介导的多巴胺、谷氨酸和GABA的释放会导致尼古丁依赖。一个 与吸烟相比，艾滋病毒感染者对尼古丁和吸烟上瘾的人数高得不成比例 对美国的普通民众来说。我们发现HIV TAT和香烟烟雾可以调节一些 它们通过一条涉及转化生长因子-β信号转导的共同途径发挥作用。TAT和转化生长因子-β改变血管内皮细胞微RNA组 支气管上皮细胞导致抑制一些关键基因参与有丝分裂和一般 巨型自噬。结合我们的报告，艾滋病毒、TAT和香烟烟雾会增加肺部 炎症，这表明改变的microRNAome可能表现为HIV和CS的启动事件 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HIV TAT和 调节呼吸道中的转化生长因子-β信号可以阻止甚至逆转肺的“炎症”，从而防止或 延缓临床疾病的发病。 基于这些观察，目标1将确定与艾滋病毒TAT和香烟有关的miRNAs的作用 吸烟相关的有丝分裂功能受损。目标2将改变有丝分裂和随后的衰老与 原代小气道上皮细胞分泌SASP相关细胞因子和DAMP的增加 体外和小动物肺特异性TAT转基因模型和HIV供体肺 吸烟者/非吸烟者。AIM 3将确定挽救TAT和转化生长因子-β效应的治疗方法 挽救有丝分裂，从而抑制应激诱导的衰老和SASP细胞因子的异常 湿透了。该提案旨在解决为艾滋病毒研究确定的主要高度优先领域之一 即艾滋病毒携带者和药物滥用患者的共病。

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.