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).

项目总结