Drug abuse and HIV-associated pulmonary vascular injury

药物滥用和 HIV 相关肺血管损伤

基本信息

批准号：
10161471
负责人：
Navneet Kaur Dhillon
金额：
$ 68.95万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161471
关键词：
AIDS/HIV problem Animal Model Apoptosis Apoptotic BCL1 Oncogene Binding Bioinformatics Biological Assay Biological Process Blood Blood Vessels Cardiopulmonary Cell Culture Techniques Cell Cycle Progression Cell Proliferation Chronic Obstructive Airway Disease Cocaine Combined Modality Therapy Data Detection Development Drug abuse Early Diagnosis Exposure to Failure Functional disorder Genes HIV HIV-1 Health Heart Heart failure Human Hyperplasia Illicit Drugs Individual Kansas Light Link Lung Macaca Mediating Medical center Microarray Analysis Modeling Pathogenesis Pathogenicity Patients Phenotype Prevalence Preventive Protein Isoforms Proteins Publishing Pulmonary Emphysema Pulmonary Hypertension RNA RNA Splicing RNA-Binding Proteins Rattus Regulation Reporting Research Research Institute Resistance Right Ventricular Dysfunction Risk Role SIV Sleep Smooth Muscle Smooth Muscle Myocytes Structure of parenchyma of lung Study models Systolic Pressure Therapeutic Intervention Transgenic Organisms Universities Untranslated RNA Up-Regulation Vascular Diseases Vascular remodeling Ventricular antiretroviral therapy base cell growth cell type cocaine exposure comorbidity differential expression drug abuser drug of abuse gene repression in vivo inhibitor/antagonist innovation intravenous drug user knock-down mRNA Expression new therapeutic target non-drug novel pre-clinical pressure prevent pulmonary arterial hypertension response tumor vascular injury

项目摘要

PROJECT SUMMARY University of Kansas Medical Center Research Institute, Inc. Advancement in antiretroviral therapy (ART) has clearly led to a serious increase in the prevalence of non- infectious cardio-pulmonary complications among HIV-infected individuals including chronic obstructive pulmonary disease (COPD) and HIV-related pulmonary arterial hypertension (HIV-PAH). 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. Significant number of previous findings including from our lab consistently suggest increased risk for pulmonary vascular dysfunction in HIV-infected individuals who abuse illicit drugs compared to HIV-infected non-drug users or un- infected drug abusers. Understanding the mechanisms by which cocaine and HIV-1 trigger pulmonary vascular injury is needed to develop preventive and early diagnosis strategies for patients at risk of HIV-PAH. Pulmonary arterial smooth muscle cells (PASMCs) are one of the primary cell-types that undergo hyperplasia during vascular remodeling. The salient finding in all our published reports is the synergistic or additive enhancement in the proliferation of PASMCs exposed to both HIV protein(s) and cocaine. Recently, long noncoding RNAs (LncRNAs) have emerged as important regulators of diverse biological process including cell proliferation and apoptosis. Based on our published and recent preliminary findings we hypothesize that alteration in the levels of lncRNA:ENST-536 in response to HIV-protein(s) and/or cocaine in smooth muscle cells promote pulmonary vascular remodeling and cardio-pulmonary complications. In the first aim we will examine if changes in the expression of ENST-536 lncRNA and its nearby tumor suppressive gene, HOXB13 regulate the HIV-Tat and cocaine mediated changes in the smooth muscle phenotype. In the second aim, we will investigate how the interactions between lncRNA ENST-536 and RNA binding protein(s) (RBP) regulate the HIV-Tat and cocaine mediated smooth muscle dysfunction.Third aim will be focused on investigating the in- vivo role of lncRNA ENST-536 and HOXB13 in the pulmonary vascular dysfunction and right ventricular failure using pre-clinical animal model 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 LncRNA, RBP and HOXB13 in the HIV-1 and/or cocaine mediated pulmonary vascular remodeling. The proposed research is significant because it will enhance our understanding of pathogenic mechanisms involved in the development of HIV-PAH and will fulfill the purpose of NOT-HL-19-677 (SEARCH: Stimulating ExplorAtory Research on HIV/AIDS Contribution to Heart, Lung, Blood and Sleep Comorbidities) in search of novel mechanisms involved in HIV-associated comorbidities.

项目概要堪萨斯大学医学中心研究所有限公司抗逆转录病毒治疗（ART）的进步显然导致非病毒感染的患病率严重增加 HIV感染者的传染性心肺并发症，包括慢性阻塞性肺病肺部疾病（COPD）和 HIV 相关肺动脉高压（HIV-PAH）。事实上，最近的报道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。重要的包括我们实验室在内的先前研究结果一致表明，肺血管疾病的风险增加与感染艾滋病毒的非吸毒者或非吸毒者相比，滥用非法药物的艾滋病毒感染者的功能障碍被感染的吸毒者。了解可卡因和 HIV-1 触发肺血管的机制需要针对有 HIV-PAH 风险的患者制定预防和早期诊断策略。肺动脉平滑肌细胞 (PASMC) 是发生增生的主要细胞类型之一在血管重塑过程中。我们所有发表的报告中的显着发现是协同或相加暴露于 HIV 蛋白和可卡因的 PASMC 增殖增强。最近，长非编码 RNA (LncRNA) 已成为包括细胞在内的多种生物过程的重要调节因子增殖和凋亡。根据我们发表的和最近的初步调查结果，我们假设平滑肌中 lncRNA:ENST-536 水平对 HIV 蛋白和/或可卡因的反应发生变化细胞促进肺血管重塑和心肺并发症。在第一个目标中，我们将检查 ENST-536 lncRNA 及其附近的肿瘤抑制基因 HOXB13 的表达是否发生变化调节 HIV-Tat 和可卡因介导的平滑肌表型变化。在第二个目标中，我们将研究 lncRNA ENST-536 和 RNA 结合蛋白 (RBP) 之间的相互作用如何调节 HIV-Tat 和可卡因介导的平滑肌功能障碍。第三个目标将集中于研究 in- lncRNA ENST-536和HOXB13在肺血管功能障碍和右心室衰竭中的体内作用使用临床前动物模型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 LncRNA、RBP 和 HOXB13 在 HIV-1 中的作用之间的潜在联系和/或可卡因介导的肺血管重塑。拟议的研究意义重大，因为它将增强我们对 HIV-PAH 发病机制的了解，并将实现 NOT-HL-19-677 的目的（搜索：刺激艾滋病毒/艾滋病贡献探索性研究心、肺、血液和睡眠合并症），寻找与 HIV 相关的新机制合并症。