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

HIV/可卡因介导的人肺血管重塑：BMPR 信号传导的作用。

基本信息

批准号：
8653959
负责人：
Navneet Kaur Dhillon
金额：
$ 30.2万
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：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653959
关键词：
Accounting Acquired Immunodeficiency Syndrome Arterial Disorder Attention Biological Models Blood Vessels Cardiac Cardiopulmonary Cardiovascular system Case Study Cell Proliferation Cessation of life Chronic Obstructive Airway Disease Cocaine Cocaine Abuse Combined Modality Therapy Coronary heart disease Data Development Diagnosis Drug abuse Exposure to Failure Family Functional disorder Future Gene Targeting Goals HIV HIV Infections HIV-1 Health Heart Heroin Human Hyperplasia Hypertrophy Individual Infection Intervention Investigation Knowledge Lead Link Lung Medial Mediating Medical MicroRNAs Mission Molecular Pathogenesis Pathway interactions Patients Play Post-Transcriptional Regulation Prevalence Probability Proteins Publishing Pulmonary Fibrosis Pulmonary Hypertension Pulmonary Vascular Resistance Receptor Signaling Regulation Reporting Research Risk Factors Role Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stream Structure of parenchyma of lung Testing Therapeutic Intervention United States United States National Institutes of Health Up-Regulation Vascular Diseases Vascular remodeling Ventricular Viral Viral Proteins Virus Work age related aged antiretroviral therapy base blood vessel occlusion bone morphogenetic protein receptors disability drug of abuse gain of function improved in vivo in vivo Model infancy innovation interstitial intravenous drug use intravenous drug user loss of function mRNA Expression migration mortality novel novel therapeutics protein expression pulmonary arterial hypertension receptor receptor expression vascular bed

项目摘要

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.

描述（由申请人提供）：该提案涉及与 HIV-1 和滥用药物相关的医疗后果（肺动脉高压）。抗逆转录病毒疗法的出现显然提高了 HIV-1 感染者的生存率，但这一进步却导致包括肺动脉高压在内的血管并发症的患病率意外增加。 HIV 相关 PAH (HPAH) 的发展会导致早期死亡，并可作为 HIV-1 感染患者死亡的独立预测因子。虽然静脉吸毒占美国所有新发艾滋病病例的三分之一，但它已被确定为诊断为 HPAH 的最常见危险因素。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塑增强，表明 IVDU 和 HIV-1 可能协同作用，导致肺动脉病。异常平滑肌细胞增殖/迁移被认为在血管重塑中发挥关键作用，导致与 PAH 相关的肺血管阻力增加，但所涉及的机制和发病机制仍不清楚。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 (pSMC) 增殖的增加具有累加效应。基于我们最近强有力的初步发现，我们假设 Tat 和可卡因介导的 pSMC 增殖增加涉及通过微小 RNA (mi-RNA) 的转录后调节下调抗增殖骨形态发生蛋白受体 (BMPR) 蛋白表达。）。这一假设将通过追求三个具体目标来检验。第一个目标是评估 HIV-Tat 和可卡因对 BMPR 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 miRNA 来描述参与 Tat 和可卡因介导的 BMPR 表达调节的转录后机制。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 pSMCs 中 miRNA 介导的 BMP/BMPR 轴调节的离体和体内研究。这些研究具有创新性，因为这将是首次尝试了解 miRNA 介导的抗增殖信号通路的作用，该信号通路涉及可卡因和病毒蛋白相互作用，导致平滑肌增生，并将这些变化与肺血管和右心功能障碍联系起来。与 HPAH 相关。拟议的研究意义重大，因为它将提供对存在和不存在可卡因滥用情况下 HPAH 发展所涉及的致病机制的更全面的了解。因此，预计未来在靶向治疗的开发以及对 HIV 相关并发症和 PAH 相关药物滥用的理解方面将取得重要进展，这与 NIH 发展基础知识的使命相关，这些基础知识将有可能有助于减轻人类残疾的负担。