Extracellular Vesicles and and HIV/cocaine associated cardiopulmonary dysfunction

细胞外囊泡和 HIV/可卡因相关的心肺功能障碍

• 批准号: 9204218
• 负责人: Navneet Kaur Dhillon
• 金额: $ 41.14万
• 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: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204218
• 关键词: AIDS/HIV problem; Animal Model; Biological Markers; Blood; Blood Vessels; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cells; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cocaine; Cocaine Users; Complement; Correlative Study; Data; Development; Diagnosis; Disease; Disease Progression; Drug abuse; Drug user; FRAP1 gene; Foundations; Functional disorder; Funding; Future; HIV; HIV Infections; HIV-1; Health; Human; Human immunodeficiency virus test; Hyperplasia; Hypertrophy; Immune; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Lead; Letters; Light; Link; Literature; Lung; Lung diseases; Macaca; Medial; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Muscle function; National Institute of Drug Abuse; PTEN gene; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Preventive Intervention; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Pathology; Rattus; Reporting; Research; Risk Factors; Role; SIV; Sampling; Severities; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Substance of Abuse; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Translations; Up-Regulation; Vascular Diseases; Vascular remodeling; Venous; Viral Proteins; antiretroviral therapy; base; blood vessel occlusion; cell type; cocaine exposure; differential expression; drug of abuse; exosome; extracellular vesicles; heart function; in vivo; innovation; interstitial; intimal medial thickening; intravenous drug user; macrophage; microvesicles; monocyte; mortality; non-drug; pressure; pulmonary arterial hypertension; response; simian human immunodeficiency virus; transcriptome sequencing; uptake; vesicular release

PROJECT SUMMARY: In general, the prolonged survival of HIV-infected patients with the use of antiretroviral (ART) therapy has resulted in an increase in the incidence of non-infectious complications including cardio-pulmonary dysfunction. In fact, recent reports suggest that pulmonary vascular remodeling and pulmonary hypertension (PH) precede the airway destruction/emphysema development and that PH and COPD coexist in HIV-infected individuals. Furthermore, IVDU has been found to be the most common risk factor of HIV-infection in the individuals diagnosed with HIV related PH (HRPAH). Our previous findings consistently suggest augmentation of pulmonary vascular dysfunction in HIV infected IVDUs compared to HIV-infected non-drug users or un-infected IVDUs . Therefore, clear understanding of how the drugs of abuse and HIV-infection either alone or in combination cause pulmonary vascular remodeling is urgently needed. Inflammation plays a crucial role in vascular remodeling associated with chronic lung and cardiovascular diseases associated with HIV-infection. We earlier observed significant perivascular inflammation in the lung sections from HIV- infected humans or simian immunodeficiency virus (SIV)-infected macaques exposed to substance of abuse including increased number of macrophages in the remodeled thickened vessels. Based on our recent preliminary findings, we hypothesize that HIV-infection and cocaine mediated alterations in the macrophage derived extracellular vesicles (EVs) promote pulmonary smooth muscle hyperplasia and vascular remodeling by regulating the proliferative signaling cascades on delivery of its cargo to smooth muscle cells . This hypothesis will be tested by pursuing four specific aims. In the first aim using RNA sequencing we will test how EV- miRnome gets influenced on exposure of HIV-infected macrophages to cocaine. In the second aim, we will evaluate the effect of these EVs on smooth muscle function using in-vitro cell-culture system. Third aim will be focused on investigating the in-vivo effect of EVs on pulmonary vascular remodeling and right heart function using HIV-Tg rat model and finally in the fourth aim we will leverage on using human samples from HIV-infected +/- cocaine abusers to correlate the changes in EVs with cardio-pulmonary dysfunction. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the macrophage derived EVs and the HIV-1 and cocaine mediated disease progression. The proposed research is significant because this will provide a critical foundation to understand the role of inflammation in the development of HIV-1 and cocaine associated cardio-vascular dysfunction while identifying specific miRNAs in EVs as biomarkers of the disease and /or new targets for preventive and therapeutic interventions in future. Therefore, the proposal is directly responsive to PAS-16-018 entitled ‘HIV/AIDS High Priority Drug Abuse Research (R01)’ to be funded by National Institute on Drug Abuse (NIDA).

项目概要： 一般来说，使用抗逆转录病毒（ART）治疗的艾滋病毒感染者的生存期延长了 导致包括心肺功能障碍在内的非感染性并发症的发生率增加。 事实上，最近的报告表明，肺血管重塑和肺动脉高压（PH）先于 气道破坏/肺气肿发展以及 PH 和 COPD 在 HIV 感染者中共存。 此外，IVDU 已被发现是个体感染 HIV 的最常见危险因素 诊断患有 HIV 相关 PH (HRPAH) 的患者 与感染艾滋病毒的非吸毒者或未感染者相比，感染艾滋病毒的 IVDU 的肺血管功能障碍 因此，要清楚地了解药物滥用和艾滋病毒感染是如何单独或共同发生的。 综合起来，炎症在肺血管重塑中起着至关重要的作用。 与艾滋病毒感染相关的慢性肺和心血管疾病相关的血管重塑。 我们之前观察到感染艾滋病毒的人的肺切片有明显的血管周围炎症，或者 感染猿猴免疫缺陷病毒（SIV）的猕猴暴露于滥用物质，包括增加 根据我们最近的初步发现，我们发现了重塑的增厚血管中巨噬细胞的数量。 发现艾滋病毒感染和可卡因介导巨噬细胞衍生的细胞外细胞的改变 囊泡（EV）通过调节肺平滑肌增生和血管重塑来促进肺平滑肌增生和血管重塑。 增殖信号传递级联将其货物传递至平滑肌细胞，这一假设将得到检验。 通过追求四个具体目标，在第一个目标中，我们将使用 RNA 测序来测试 EV-miRnome 是如何获得的。 对 HIV 感染的巨噬细胞暴露于可卡因的影响在第二个目标中，我们将评估其效果。 第三个目标将集中在使用体外细胞培养系统对这些电动汽车的平滑肌功能进行研究。 使用 HIV-Tg 研究 EV 对肺血管重塑和右心功能的体内影响 大鼠模型，最后在第四个目标中，我们将利用感染艾滋病毒的人体样本+/-可卡因 这些研究具有创新性，可以帮助滥用者将 EV 的变化与心肺功能障碍联系起来。 因为据我们所知，这将是第一次尝试了解两者之间的潜在联系 巨噬细胞衍生的 EV 以及 HIV-1 和可卡因介导的疾病进展。 意义重大，因为这将为理解炎症在 HIV-1 和可卡因相关心血管功能障碍的发展，同时识别特定的 miRNA EV 作为疾病的生物标志物和/或未来预防和治疗干预的新目标。 因此，该提案直接响应题为“艾滋病毒/艾滋病高度优先药物滥用”的 PAS-16-018 研究（R01）”由国家药物滥用研究所（NIDA）资助。