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)感染者的存活率随着 抗逆转录病毒治疗显然导致了非感染性并发症患病率的严重增加。在……里面 在这方面，最具破坏性的后遗症之一是#年发生的肺动脉高压。 艾滋病毒感染者(HPAH)。静脉注射毒品(IVDU)占所有新增艾滋病病例的三分之一 在美国，并已被确定为最常见的风险因素个人诊断为 HPAH。我们最近的发现显示HIV感染的肺组织中肺血管重塑增强 来自静脉注射海洛因和/或可卡因滥用者和感染的猕猴 吗啡表明，非法药物和HIV-1可能共同作用，导致肺动脉病。 此外，感染了SIV的吗啡处理的猕猴被发现有更多的细胞凋亡 早期病变中的内皮细胞，而通过活跃的内皮细胞增殖而完全闭塞 猴免疫缺陷(SIV) 晚期丛状皮损中可见细胞。 这一观察结果进一步得到了我们内部- 体外研究结果显示，人肺细胞的凋亡增加，随后显著增加增殖 与HIV同时治疗的内皮细胞- 转录反式激活因子 (TAT)蛋白质和吗啡 与任何一种单独治疗相比。根据我们最近的发现，我们研究的假设是 肺内皮细胞暴露于人类免疫缺陷病毒蛋白(S)和吗啡的联合诱导 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和吗啡在氧化应激介导的内皮细胞大量自噬调节中的作用。在 第二个目的，我们建议描述自噬/有丝分裂吞噬在TAT和吗啡介导的增强中的作用。 扩散。第三个目标将集中在体内研究多环芳烃和自噬在HIV-1TG大鼠或 没有接触过吗啡。这些研究是创新的，因为据我们所知，这将是 首次尝试了解吗啡中自噬/有丝分裂吞噬的作用与 HIV-蛋白介导的抗凋亡促进增殖。拟议的研究将加强我们的 了解HPAH发病的基本机制，因此直接 对RFA-HL-14-024的反应(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)。