Drug abuse and HIV-associated pulmonary vascular injury

药物滥用和 HIV 相关肺血管损伤

• 批准号: 10330405
• 负责人: Navneet Kaur Dhillon
• 金额: $ 60.05万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 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/10330405
• 关键词: AIDS/HIV problem; Animal Model; Apoptosis; Apoptotic; BCL1 Oncogene; BCL2L1 gene; Binding; Bioinformatics; Biological Assay; Biological Process; Blood; Blood Vessels; Cardiopulmonary; Cell Culture Techniques; Cell Cycle Progression; Cell Proliferation; Chronic Obstructive Pulmonary Disease; Cocaine; Combined Modality Therapy; Data; Detection; Development; Drug abuse; Early Diagnosis; Exposure to; Functional disorder; Genes; HIV; HIV-1; Health; Heart; 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; innovation; intravenous drug user; knock-down; lung vascular injury; mRNA Expression; new therapeutic target; non-drug; novel; pre-clinical; prevent; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary vascular remodeling; response; right ventricular failure; tumor; vascular injury

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.

项目摘要 堪萨斯大学医学中心研究所，公司 抗逆转录病毒疗法（ART）的进步显然导致了非 - 艾滋病毒感染的个体中的感染性心肺并发症，包括慢性阻塞性 肺疾病（COPD）和HIV相关的肺动脉高压（HIV-PAH）。实际上，最近的报告 建议肺血管重塑和肺动脉高压（pH）在气道之前 破坏/肺气肿的发展以及pH和COPD在受HIV感染的个体中共存。重要的 以前的发现（包括我们实验室）的数量始终表明肺血管的风险增加 与艾滋病毒感染的非药物使用者相比，滥用非法药物的艾滋病毒感染者的功能障碍 被感染的滥用药物。了解可卡因和HIV-1触发肺血管的机制 为患有HIV-PAH风险的患者制定预防和早期诊断策略需要伤害。 肺动脉平滑肌细胞（PASMC）是经历增生的主要细胞类型之一 在血管重塑期间。我们所有已发表的报告中的显着发现是协同或添加剂 暴露于HIV蛋白和可卡因的PASMC增殖的增强。最近，很长 非编码RNA（LNCRNA）已成为多种生物学过程的重要调节剂，包括细胞 增殖和凋亡。根据我们发表的最新初步发现，我们假设 LNCRNA水平的改变：ENST-536响应于平滑肌中的HIV蛋白质和/或可卡因 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表达的变化及其附近抑制基因HOXB13 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与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。 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 首先尝试了解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。拟议的研究很重要，因为它将 增强我们对HIV-PAH发育中涉及的致病机制的理解，并将实现 非HL-19-677的目的（搜索：刺激艾滋病毒/艾滋病贡献的探索性研究 心脏，肺，血液和睡眠合并症）寻找与HIV相关的新机制 合并症。