Mechanisms of defective mitophagy and cellular senescence in HIV associated COPD

HIV 相关 COPD 中线粒体自噬缺陷和细胞衰老的机制

基本信息

批准号：
9978609
负责人：
HOSHANG JEHANGIR UNWALLA
金额：
$ 46.92万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978609
关键词：
Abbreviations Accounting Address Aging Air Animals Area Bacterial Pneumonia Bronchoalveolar Lavage CCL2 gene CD4 Lymphocyte Count Cell Aging Cells Chimera organism Chronic Chronic Obstructive Airway Disease Clinical Cystic Fibrosis Transmembrane Conductance Regulator Data Development Disease Dopamine Epithelial Cells Event General Population Genes Glutamates Goals HIV HIV Infections Homeostasis Human Impairment In Vitro Inflammaging Inflammation Interleukin-1 Interleukin-6 Liquid substance Lung Lung Inflammation Lung diseases Measures Mediating MicroRNAs Mitochondria Mitochondrial DNA Molecular Morbidity - disease rate Nicotine Nicotine Dependence Oxidative Stress PINK1 gene Pathway interactions Patients Pattern Pharmacology Phenotype Play Pneumocystis Infections Pneumonia Population Predisposing Factor Production Pulmonary Hypertension RNA Reporting Research Respiratory physiology Response Elements Risk Factors Role SIRT1 gene Severities Signal Transduction Smoker Smoking Status Stress Substance abuse problem TGFBR2 gene TNF gene Therapeutic Tissues Tobacco smoke Transactivation Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Transgenic Model United States airway epithelium antiretroviral therapy aptamer autocrine base bronchial epithelium cell type cigarette smoke cigarette smoking comorbidity cytokine functional decline gamma-Aminobutyric Acid in vivo mortality non-smoker paracrine parkin gene/protein prevent senescence

项目摘要

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.

项目摘要在衰老的HIV感染人群中，合并症是发病率和死亡率的重要决定者。肺部肺炎，COPD和肺动脉高压等肺部疾病已成为显着的患有艾滋病毒的人的合并症。 COPD仍然是HIV感染的重要合并症即使抗逆转录病毒疗法已成功恢复CD4细胞计数并减少肺炎藻的感染。艾滋病毒是COPD的独立危险因素，即使补偿吸烟地位。衰老相关的促炎细胞因子在慢性炎症中起着重要作用这是COPD的标志。线粒体受损会导致去极化有缺陷的线粒体积累这表明ROS的产生增加并释放相关的分子模式（潮湿）与感应相关的秘密表型（SASP）相关细胞因子的伴随增加。吸烟是艾滋病毒感染者中尼古丁成瘾的主要手段。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性。一个相比美国的普通人群。我们表明艾滋病毒和香烟烟介导了一些它们通过参与TGF-β信号传导的共同途径的影响。 tat和tgf-β改变支气管上皮细胞，导致抑制某些参与线粒体和一般的关键基因宏观哲学。结合我们的报道说艾滋病毒和香烟烟增加了肺炎症，这表明变化的微洋母细胞可能表现为HIV和CS中的启动事件相关的COPD随着艾滋病毒吸烟者观察到的发作严重程度增加。因此中和HIV TAT和调节气道中的TGF-β信号传导可以阻止甚至反向肺“发炎”，从而防止或减慢临床疾病的发作。基于这些观察结果，AIM 1将确定与HIV TAT和香烟有关的miRNA的作用烟与线粒体相关。 AIM 2将与线粒体变化，并随之而来的感应 SASP相关的细胞因子和潮湿的分泌增加了原发性小气道上皮细胞（SAEC）体外和小动物肺特异性TAT转基因模型和HIV的供体肺吸烟者/非吸烟者。 AIM 3将确定拯救TAT和TGF-β的影响的治疗方法挽救线粒体，因此抑制应激诱导的感应和异常的SASP细胞因子和潮湿。该提案的目标将解决艾滋病毒研究确定的主要高优先级领域之一即艾滋病毒和滥用毒品的人的合并症。