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).

项目摘要 人类免疫缺陷病毒（HIV-1）感染了人类免疫缺陷病毒（HIV-1）的生存率 抗逆转录病毒疗法显然导致了非感染并发症患病率的严重增加。在 这方面，最具破坏性的后遗症之一是肺动脉高压的发展 艾滋病毒感染者（HPAH）。静脉吸毒（IVDU）占所有新艾滋病案例的三分之一 在美国，已被确定为被诊断为患者 hpah。我们最近的发现表明在感染HIV的肺组织中增强的肺血管重塑 来自IV海洛因和/或可卡因施虐者，以及暴露于感染的猕猴 吗啡表明非法药物和HIV-1有可能协同起作用引起肺动脉疾病。 此外，发现经SIV感染的吗啡处理的猕猴的凋亡数量增加 内皮细胞在早期病变中，而通过主动增殖内皮的完全闭塞 猿猴免疫缺陷（SIV） 在晚期的丛状病变中观察到细胞。 我们的观察进一步支持了这一观察 体外发现显示凋亡增强，然后显着增加人类肺的增殖 内皮细胞同时治疗HIV- 转录剂 （TAT）蛋白质和吗啡 与单独的治疗相比。根据我们最近的发现，我们研究的假设是 肺内皮细胞与HI​​V蛋白（S）和吗啡的结合暴露导致诱导 自噬会导致内皮细胞增殖和严重的肺血管重塑。 该假设将通过追求三个具体目标来检验。在第一个目的中，我们将评估HIV的影响 TAT和吗啡在氧化应激介导的内皮细胞中大量自噬的调节。在 第二个目的，我们建议描述自噬/线粒能在TAT和吗啡介导的增强中的作用 增殖。第三个目标将集中于对HIV-1 TG大鼠PAH和自噬的体内调查 没有吗啡暴露。这些研究具有创新性，因为据我们所知， 首先尝试了解自噬/线索在吗啡中的作用和 HIV蛋白介导的抗凋亡抗性增强了增殖。拟议的研究将增强我们的 理解HPAH发病机理所涉及的基本机制，因此是直接的 对RFA-HL-14-024的反应（与HIV相关心脏，肺和血液的发病机理的基础研究 （HLB）成人和儿童的疾病）。