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：
10188625
负责人：
HOSHANG JEHANGIR UNWALLA
金额：
$ 46.93万
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/10188625
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 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 pulmonary function pulmonary function decline 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.

项目概要在老龄化艾滋病毒感染人群中，合并症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疾病艾滋病毒感染者的合并症仍然是艾滋病毒感染者的一个重要合并症。尽管抗逆转录病毒治疗已成功恢复 CD4 细胞计数并减少患者肺孢子虫感染是慢性阻塞性肺病的一个独立危险因素，即使吸烟得到补偿。衰老相关的促炎细胞因子在慢性炎症中发挥重要作用。这是慢性阻塞性肺病的一个标志，线粒体自噬受损会导致去极化缺陷线粒体的积累。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方式。尼古丁介导的多巴胺、谷氨酸和 GABA 释放的影响导致尼古丁依赖。相比之下，大量艾滋病毒感染者对尼古丁和吸烟成瘾我们发现 HIV Tat 和香烟烟雾介导了一些影响。它们通过涉及 TGF-β 信号传导的共同途径发挥作用，从而改变 microRNAome。支气管上皮细胞导致一些参与线粒体自噬和一般的关键基因受到抑制结合我们的报告，HIV Tat 和香烟烟雾会增加肺功能。炎症，这表明改变的 microRNAome 可能表现为 HIV 和 CS 的起始事件在艾滋病毒吸烟者中观察到的慢性阻塞性肺病与发病严重程度增加有关，因此可以中和艾滋病毒。调节气道中的 TGF-β 信号传导可以阻止甚至逆转肺部“炎症”，从而预防或逆转减缓临床疾病的发生。基于这些观察结果，目标 1 将确定 miRNA 在 HIV Tat 和香烟中的作用目标 2 将线粒体自噬改变和随之而来的衰老与烟雾相关。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 Tat 转基因模型和 HIV 供体肺目标 3 将确定挽救 Tat 和 TGF-β 对吸烟者/非吸烟者的影响的治疗方法。拯救线粒体自噬，从而抑制应激诱导的衰老和异常的 SASP 细胞因子，该提案的目标将解决艾滋病毒研究确定的主要高度优先领域之一。即艾滋病毒感染者和药物滥用者的合并症。