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。

• 批准号: 8410671
• 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
• 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/8410671
• 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

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. PUBLIC HEALTH RELEVANCE: The proposed research will have an important positive impact on human health because the identified mechanism(s) and the molecules involved are expected to provide new targets for therapeutic interventions that will aid the growing number of HIV-infected and/or intravenous drug users, who acquire pulmonary arterial hypertension. In addition, the results will fundamentally advance the field of cardio-pulmonary vascular research in general.

描述（由申请人提供）： 这是一项涉及与HIV-1和滥用药物有关的医疗后果（肺动脉高压）的提案。抗逆转录病毒疗法的出现明显提高了HIV-1感染者的生存率，但这一进展却导致了包括肺动脉高压在内的血管并发症发病率的意外增加。HIV相关PAH（HPAH）的发展导致早期死亡，并作为HIV-1感染患者死亡的独立预测因子。虽然静脉注射毒品占美国所有艾滋病新发病例的三分之一，但它已被确定为艾滋病的主要传播途径。 最常见的危险因素在个人诊断为HPAH。此外，我们最近的研究表明，增强肺血管重塑艾滋病毒感染的肺组织从静脉注射海洛因和/或可卡因滥用者表明，静脉吸毒和HIV-1可能共同作用，导致肺动脉病。认为异常平滑肌细胞增殖/迁移在血管重塑中发挥关键作用，导致PAH相关肺血管阻力增加，但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（pSMCs）增殖增加的叠加效应。基于我们最近强有力的初步研究结果，我们假设这种达特和可卡因介导的pSMC增殖的增加涉及通过微RNA（mi-RNA）的转录后调节下调抗增殖骨形态发生蛋白受体（BMPR）蛋白的表达。这一假设将通过追求三个具体目标来检验。第一个目的是研究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，我们提出通过调节特定的miRNA来描述参与达特和可卡因介导的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离体和体内研究miRNA介导的pSMCs BMP/BMPR轴调节。这些研究是创新的，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，该通路参与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。拟议的研究是重要的，因为它将提供一个更完整的了解致病机制参与的发展HPAH的存在和不存在可卡因滥用。因此，预计未来在靶向治疗的开发和对与HIV和药物滥用相关的PAH并发症的理解方面将取得重要进展，这与NIH开发基础知识的使命相关，这些知识可能有助于减轻人类残疾的负担。 公共卫生相关性： 拟议的研究将对人类健康产生重要的积极影响，因为所确定的机制和所涉及的分子预计将为治疗干预提供新的靶点，这将有助于越来越多的艾滋病毒感染者和/或静脉吸毒者获得肺动脉高压。此外，这些结果将从根本上推动心肺血管研究领域的发展。