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：
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
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/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

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. 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）：这是一项针对与HIV-1和滥用药物有关的医疗后果（肺动脉高压）的建议。抗逆转录病毒疗法的出现显然导致了HIV-1感染个体的生存率提高，但这种进步导致血管并发症（包括肺动脉高压）的血管并发症患病率的意外增加。 HIV相关PAH（HPAH）的发展导致早期死亡率，并作为感染HIV-1的患者的死亡的独立预测。虽然静脉吸毒使用占美国所有新艾滋病案例的三分之一，但已被确定为被诊断为HPAH的个体中最常见的危险因素。此外，我们最近的研究表明，来自IV海洛因和/或可卡因滥用者的HIV感染的肺组织中肺血管重塑的增强表明，IVDU和HIV-1可能会协同起作用会引起肺动脉炎。平滑肌细胞增殖/迁移异常被认为在血管重塑中起关键作用，从而导致与PAH相关的肺血管抗性增加，但涉及的机制和发病机理仍然难以捉摸。我们最近的研究支持可卡因对HIV-TAT介导的人类肺动脉平滑肌细胞增殖的增加（PSMC）。根据我们最近的强烈初步发现，我们假设这种TAT和可卡因介导的PSMC的增殖涉及抗增殖性骨形态发生蛋白受体（BMPR）蛋白通过微生NAS的转录调节（MI-RNAS）的调节（MI-RNAS）（MI-RNAS）（MI-RNA）（MI-RNA）（MI-RNA ）。该假设将通过追求三个具体目标来检验。在第一个目标中，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miRNA的调节来描述参与TAT和可卡因介导的BMPR表达调节的转录后机制。为了进一步确认HIV-1和可卡因在BMPR轴上的相互作用，第三个目标将集中于PSMC中miRNA介导的BMP/BMPR轴的EX-VIVO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对可卡因和病毒蛋白相互作用的抗增殖信号通路的miRNA介导的作用，从而导致平滑肌增生并将这些变化与肺血管和右心脏功能障碍联系起来与HPAH相关。拟议的研究很重要，因为它将在存在和不存在可卡因滥用的情况下对涉及HPAH发展的致病机制提供更完整的理解。因此，未来期望与NIH发展基本知识的使命相关的靶向疗法的发展以及对与艾滋病毒和虐待药物相关的并发症的理解以及对虐待药物相关的并发症的重要进展，这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，因为所鉴定的机制和所涉及的分子有望为治疗干预措施提供新的目标，这将有助于越来越多的HIV感染和/或静脉内吸毒者（他们）获得肺动脉高压。此外，总体上将从根本上推进心肺血管研究的领域。