HIV/Cocaine mediated human pulmonary vascular remodeling: Role of BMPR signaling.

描述(由申请人提供)： 这是一项涉及与艾滋病毒-1和滥用药物有关的医学后果(肺动脉高压)的提案。抗逆转录病毒疗法的出现显然提高了HIV-1感染者的存活率，但这一进步也意外地增加了包括肺动脉高压在内的血管并发症的患病率。HIV相关PAH(HPAH)的发展导致早期死亡，并作为感染HIV-1患者死亡的独立预测因子。虽然静脉注射毒品占美国所有新增艾滋病病例的三分之一，但它已被确定为 在被诊断为HPAH的个体中最常见的危险因素。此外，我们最近的研究表明，静脉注射海洛因和/或可卡因滥用者感染HIV的肺组织中肺血管重构增强，表明IVDU和HIV-1可能共同作用导致肺动脉病变。异常的平滑肌细胞增殖/迁移被认为在血管重构中起关键作用，导致PAH相关的肺血管阻力增加，但涉及的机制和发病机制尚不清楚。我们最近的研究支持可卡因对HIV-TAT介导的人肺动脉平滑肌细胞(PSMCs)增殖的相加作用。根据我们最近强有力的初步发现，我们假设TAT和可卡因介导的PSMCs增殖增加涉及到通过微RNA(mi-RNAs)转录后调控下调抗增殖的骨形态发生蛋白受体(BMPR)蛋白的表达。这一假设将通过追求三个具体目标来检验。在第一个目的中，我们将评估HIV-TAT和可卡因对BMPRs表达及其下游信号通路的影响。在第二个目标中，我们建议通过调节特定的miRNAs来描述TAT和可卡因介导的BMPR表达调控的转录后机制(S)。为了进一步证实HIV-1和可卡因在BMPR轴上的相互作用，第三个目标将集中在体外和体内研究miRNA介导的PSMCs中BMP/BMPR轴的调节。这些研究具有创新性，因为这将是首次尝试了解miRNA对抗增殖信号通路的影响，这些信号通路涉及可卡因和病毒蛋白的相互作用，导致平滑肌增生，并将这些变化与HPAH相关的肺血管和右心功能障碍联系起来。这项拟议的研究具有重要意义，因为它将更全面地了解在存在和不存在可卡因滥用的情况下发生HPAH的致病机制。因此，在开发有针对性的治疗方法和了解与艾滋病毒相关的并发症和与PAH相关的药物滥用方面，预计未来将取得重要进展，这与NIH发展基础知识的使命相关，这可能有助于减轻人类残疾的负担。

DESCRIPTION (provided by applicant): This is a proposal dealing with medical consequences (pulmonary arterial hypertension) associated with HIV-1 and drugs of abuse. The advent of antiretroviral therapy has clearly led to improved survival among HIV-1 infected individuals yet this advancement has resulted in unexpected increase in the prevalence of vascular complications including pulmonary arterial hypertension. Development of HIV-associated PAH (HPAH) results in early mortality and serves as an independent predictor of death in patients infected with HIV-1. While intravenous drug use accounts for one-third of all new cases of AIDS in the United States, it has been identified as the most common risk factor in the individuals diagnosed with HPAH. Furthermore, our recent study showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers indicate that IVDU and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Abnormal smooth muscle cell proliferation/migration are considered to play a key role in vascular remodeling leading to increased pulmonary vascular resistance associated with PAH but the mechanisms and pathogenesis involved remain elusive. Our recent study supports an additive effect of cocaine on the HIV-Tat mediated increase in proliferation of human pulmonary arterial smooth muscle cells (pSMCs). Based on our recent strong preliminary findings we hypothesize that this Tat and cocaine mediated increase in proliferation of pSMCs involves down-modulation of anti-proliferative bone morphogenetic protein receptor (BMPR) protein expression through post-transcriptional regulation by micro-RNAs (mi-RNAs). This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV-Tat and cocaine on the BMPRs expression and its down-stream signaling pathways. In the second aim, we propose to delineate the post-transcriptional mechanism(s) involved in Tat and cocaine mediated regulation of BMPR expression, through modulation of specific miRNAs. In order to further confirm the interactions of HIV-1 and cocaine on BMPR axis, the third aim will be focused on ex-vivo and in-vivo investigation of miRNA mediated regulation of BMP/BMPR axis in pSMCs. These studies are innovative because this will be a first attempt to understand the miRNA mediated effect on anti-proliferative signaling pathways involved in the interaction of cocaine and viral protein that results in smooth muscle hyperplasia and linking these changes to the pulmonary vascular and right heart dysfunction associated with HPAH. The proposed research is significant because it will provide a more complete understanding of pathogenic mechanisms involved in the development of HPAH in the presence and absence of cocaine abuse. Thus, important advances in the development of targeted therapies and understanding of complications associated with HIV and drugs of abuse associated PAH are expected in the future which is relevant to the NIH's mission of developing fundamental knowledge that will potentially help reduce the burdens of human disability.