Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling

阿片类药物滥用对 HIV 介导的肺血管重塑的影响

• 批准号: 9204520
• 负责人: Navneet Kaur Dhillon
• 金额: $ 51.4万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204520
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adult; Antioxidants; Apoptosis; Apoptotic; Arterial Disorder; Autophagocytosis; Autophagosome; Basic Science; Blood Vessels; Cardiopulmonary; Cardiovascular system; Cells; Child; Cocaine; Complement; Complex; Development; Diagnosis; Disease; Drug abuse; Endothelial Cells; Excision; Exposure to; Gene Expression; Genes; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Health; Heart; Hematological Disease; Heroin; Human; Illicit Drugs; Immunologic Deficiency Syndromes; In Vitro; Incidence; Individual; Intervention; Investigation; Lesion; Lesion by Stage; Link; Lung; Macaca; Mediating; Mitochondria; Molecular; Morbidity - disease rate; Morphine; Naloxone; Narcotic Antagonists; Opioid; Organelles; Oxidative Stress; Pathogenesis; Patients; Prevalence; Proliferating; Proteins; Pulmonary vessels; Rattus; Regulation; Reporting; Research; Resistance; Risk Factors; Role; SIV; Severities; Signal Transduction; Source; Staging; Structure of parenchyma of lung; Testing; Therapeutic Intervention; Trans-Activators; Transgenic Organisms; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular remodeling; Viral; Viral Proteins; Virus; antiretroviral therapy; attenuation; base; cytotoxic; drug of abuse; improved; in vivo; inhibitor/antagonist; innovation; intravenous drug use; intravenous drug user; knock-down; mortality; non-drug; novel; novel therapeutics; opioid abuse; prevent; pulmonary arterial hypertension

Project Summary Improved survival among human immuno-deficiency virus (HIV-1) infected individuals with the advent of antiretroviral therapy has clearly led to serious increase in the prevalence of noninfectious complications. In this regard, one of the most devastating sequelae is the development of pulmonary arterial hypertension in HIV-infected individuals (HPAH). Intravenous drug use (IVDU) accounts for one-third of all new cases of AIDS in the United States and has been identified as the most common risk factor in the individuals diagnosed with HPAH. Our recent findings showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers and in -infected macaques exposed to morphine indicate that illicit drugs and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Furthermore, SIV-infected morphine treated macaques were found to have increased number of apoptotic endothelial cells in the early stage lesions, whereas complete occlusion by actively proliferating endothelial simian immunodeficiency (SIV) cells was observed in the advanced stage plexiform lesions. This observation was further supported by our in- vitro findings showing enhanced apoptosis followed by significantly increased proliferation of human pulmonary endothelial cells on simultaneous treatment with HIV- transactivator of transcription (Tat) protein and morphine compared to either treatment alone. Based on our recent findings, the hypothesis of our study is that the combined exposure of pulmonary endothelial cells to HIV-protein(s) and morphine results in the induction of autophagy that leads to enhanced proliferation of endothelial cells and severe pulmonary vascular remodeling. This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV- Tat and morphine on the oxidative stress mediated regulation of bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of autophagy/mitophagy in Tat and morphine mediated enhanced proliferation. Third aim will be focused on in-vivo investigation of PAH and autophagy in HIV-1 Tg rats with or without morphine exposure. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the role of autophagy/mitophagy in the morphine and HIV-proteins mediated apoptosis resistant enhanced proliferation. The proposed research will enhance our understanding of the fundamental mechanisms involved in the pathogenesis of HPAH and therefore is directly responsive to RFA-HL-14-024 (Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children).

项目概要 随着人类免疫缺陷病毒 (HIV-1) 感染者的出现，提高了生存率 抗逆转录病毒治疗显然导致非感染性并发症发生率严重增加。在 在这方面，最具破坏性的后遗症之一是肺动脉高压的发生 HIV 感染者 (HPAH)。静脉吸毒 (IVDU) 占所有新发艾滋病病例的三分之一 在美国，已被确定为被诊断患有此病的个体中最常见的危险因素 肺动脉高压。我们最近的研究结果表明，HIV 感染的肺组织中的肺血管重塑增强 来自静脉注射海洛因和/或可卡因滥用者以及接触过的受感染猕猴 吗啡表明非法药物和 HIV-1 可能协同作用，导致肺动脉病。 此外，感染 SIV 的吗啡处理的猕猴被发现细胞凋亡数量增加。 早期病变中的内皮细胞，而通过活跃增殖的内皮细胞完全闭塞 猿猴免疫缺陷（SIV） 在晚期丛状病变中观察到细胞。 我们的研究进一步支持了这一观察结果 体外研究结果显示细胞凋亡增强，随后人肺细胞增殖显着增加 内皮细胞同时接受 HIV 治疗 转录反式激活子 (Tat) 蛋白质和吗啡 与单独治疗相比。根据我们最近的发现，我们的研究假设是 肺内皮细胞同时暴露于 HIV 蛋白和吗啡会导致诱导 自噬导致内皮细胞增殖增强和严重的肺血管重塑。 这一假设将通过追求三个具体目标来检验。在第一个目标中，我们将评估艾滋病毒的影响 Tat 和吗啡对内皮细胞氧化应激介导的大量自噬调节的影响。在 第二个目标，我们建议描述自噬/线粒体自噬在 Tat 和吗啡介导的增强中的作用 增殖。第三个目标将集中于患有或患有 HIV-1 Tg 大鼠的 PAH 和自噬的体内研究 没有吗啡暴露。这些研究具有创新性，因为据我们所知，这将是 首次尝试了解自噬/线粒体自噬在吗啡和线粒体自噬中的作用之间的潜在联系 HIV蛋白介导的细胞凋亡抗性增强了增殖。拟议的研究将增强我们的 了解 HPAH 发病机制的基本机制，因此直接 响应 RFA-HL-14-024（HIV 相关心、肺和血液发病机制的基础研究） （HLB）成人和儿童疾病）。