Drug abuse and HIV-associated pulmonary vascular injury

项目摘要 堪萨斯大学医学中心研究所。 抗逆转录病毒疗法（ART）的进步显然导致非病毒性肝炎的流行率严重增加， HIV感染者的感染性心肺并发症，包括慢性阻塞性肺疾病 肺疾病（COPD）和HIV相关的肺动脉高压（HIV-PAH）。事实上，最近的报道 提示肺血管重构和肺动脉高压（PH）先于气道 在HIV感染者中PH和COPD共存。显著 包括我们实验室在内的许多先前的发现一致表明肺血管疾病的风险增加 滥用非法药物的艾滋病毒感染者与艾滋病毒感染的非吸毒者或未吸毒者相比， 受感染的吸毒者了解可卡因和HIV-1触发肺血管的机制 因此，有必要为有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（pulmonary arterial smooth muscle cells，PASMCs）是发生增生的主要细胞类型 在血管重塑过程中。在我们所有发表的报告中，突出的发现是协同或相加 增强暴露于HIV蛋白和可卡因的PASMC的增殖。近日，长 非编码RNA（LncRNA）已成为多种生物过程的重要调节因子，包括细胞内的 增殖和凋亡。根据我们发表的和最近的初步研究结果，我们假设， 平滑肌中响应HIV蛋白和/或可卡因的lncRNA：ENST-536水平的改变 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 检测ENST-536 lncRNA及其附近的肿瘤抑制基因HOXB 13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。第二个目标，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。第三个目的将集中在调查在- lncRNA ENST-536和HOXB 13在肺血管功能障碍和右心室衰竭中的体内作用 这些研究是创新的，因为据我们所知， 首次尝试了解LncRNA，RBP和HOXB 13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。这项研究意义重大，因为它将 加强我们对HIV-PAH发展中致病机制的理解， NOT-HL-19-677的目的（《促进对艾滋病毒/艾滋病贡献的探索性研究》） 心、肺、血液和睡眠合并症），以寻找与HIV相关的 合并症。

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.