Neutrophil dysregulation as a driving mechanism of cardiovascular disease in HIV-1-infection

中性粒细胞失调是 HIV-1 感染者心血管疾病的驱动机制

基本信息

批准号：
9341375
负责人：
Zdenek Hel
金额：
$ 57.3万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341375
关键词：
Acquired Immunodeficiency Syndrome Address Arterial Fatty Streak Atherosclerosis Automobile Driving Bacterial Translocation Blood Vessels Bone Marrow Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell Death Cells Cerebrovascular Disorders Chronic Chronic Disease Clinical Trials Consensus Coronary artery DNA Data Development Disease Disease Progression Emergency Situation Epithelial Event Exposure to Genetic Transcription Granulopoiesis HIV Infections HIV-1 Immune Immunologics Individual Infection Inflammation Inflammatory Intervention Intestinal Mucosa Intestines Leukocytes Link Longitudinal prospective study Mediator of activation protein Methods Morbidity - disease rate Mucous Membrane Myocardial Infarction Myocardial Ischemia Neutrophil Activation Patients Pharmacology Phenotype Population Process Production Prognostic Marker Proteins Publishing Recruitment Activity Reporting Research Research Personnel Retrospective Studies Risk Risk Factors Role Stimulus Stroke Testing Thrombus Vascular Diseases antiretroviral therapy arterial stiffness base cardiovascular disorder risk cell type cohort cytokine endothelial dysfunction extracellular intimal medial thickening macrophage microbial mortality neutrophil novel novel diagnostics novel therapeutic intervention progression marker randomized trial release factor scaffold translational impact virology

项目摘要

7. PROJECT SUMMARY / ABSTRACT. HIV infection conveys a 1.5 – 2 fold increased risk for atherosclerotic cardiovascular diseases (CVD). HIV-1-infected individuals are disproportionately impacted by CVD with increased carotid artery intima- medial thickening, subclinical coronary artery atherosclerosis, endothelial dysfunction, arterial stiffness, and silent ischemic heart disease compared to uninfected controls. CVD and other chronic diseases are increasingly replacing AIDS-related complications as the most common causes of morbidity and mortality in ART-treated patients. There is a widespread consensus that chronic inflammation resulting from microbial translocation, persisting despite successful virological control, is responsible for this excess risk. However, the specific mechanisms and mediators of this process are not well understood. Neutrophils, the most abundant leukocyte population, have recently emerged as critical contributors to atherosclerosis and thrombotic disorders. Following activation, a subset of neutrophils undergoes a specific type of cell death referred to as NETosis characterized by a release of large extracellular neutrophil extracellular traps (NETs) composed of chromosomal DNA and neutrophil granular proteins. These NETs provide the stimulus and the scaffold for thrombus formation and prime macrophages for production of cytokines that amplify immune cell recruitment in atherosclerotic plaques. We have demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. The accumulated evidence strongly suggests that neutrophils undergoing NETosis accelerate CVD progression in HIV-1 infection. The overall objectives of this proposal are to: 1) define the role of activated neutrophils and NETosis as driving mechanisms of CVD in HIV-1-infected individuals, and 2) identify the mechanisms responsible for chronic neutrophilic activation in HIV-1-infected individuals in order to reveal specific checkpoints for intervention. Our central hypothesis is that chronic inflammation in intestinal mucosal tissue of HIV-1-infected individuals results in a release of factors inducing neutrophil activation and accelerated recruitment from bone marrow. The emerging neutrophil population has higher capacity to undergo NETosis following activation by bacterial products leaking across the damaged intestinal barrier. NETs released from activated neutrophils promote the progression of vascular dysfunction in HIV-1 infection. The overall objectives will be accomplished in three specific aims: 1) Determine the extent to which neutrophil activation and NETosis predict the progression of vascular dysfunction in HIV-1-infected individuals; 2) Define the mechanisms of chronic systemic neutrophil activation in HIV-1 infection; and 3) Define the neutrophil-based prognostic markers that are associated with vascular disease-related morbid events in HIV-1-infection. We expect that the proposed project will fundamentally advance our understanding of primary mechanisms of inflammation-driven vascular disease in HIV-1 infection. The definition of mechanisms driving the progression of vascular diseases in HIV-1-infected individuals will have significant translational impact and serve as a basis for novel diagnostic and therapeutic approaches.

7。项目摘要 /摘要。 HIV感染传达了1.5 - 2倍的动脉粥样硬化心血管疾病的风险（CVD）。 HIV-1感染的个体受CVD的影响不成比例，颈动脉内膜增加培养基增厚，亚临床冠状动脉粥样硬化，内皮功能障碍，动脉僵硬和与未感染的对照相比，无声缺血性心脏病。 CVD和其他慢性疾病是越来越代替与艾滋病相关的并发症是发病和死亡率最常见的原因经过艺术治疗的患者。有一个宽度共识，即微生物引起的慢性感染迁移，持续存在的目的地成功的病毒学控制，负责这种超出风险。但是，该过程的特定机制和调解人尚不清楚。中性粒细胞是最丰富的白细胞种群，最近成为关键的贡献者动脉粥样硬化和血栓性疾病。激活后，中性粒细胞的一部分经历了特定细胞死亡的类型称为Netosis，其特征是大细胞外嗜中性粒细胞释放由染色体DNA和中性粒细胞颗粒蛋白组成的细胞外陷阱（网）。这些网提供血栓形成的刺激和支架在动脉粥样硬化斑块中扩增免疫细胞募集的细胞因子。我们已经证明了来自HIV-1感染者的中性粒细胞显示活化的表型，特定的转录谱，脱粒率提高，并具有高能力发生Netosis。积累的证据很大表明患有Netosis的中性粒细胞在HIV-1感染中加速了CVD进展。总体该提案的目标是：1）将激活的中性粒细胞和Netosis的作用定义为驾驶 HIV-1感染个体中CVD的机制，以及2）确定负责慢性的机制 HIV-1感染的个体中性粒细胞激活，以揭示干预的特定检查点。我们的中心假设是HIV-1感染个体的肠粘膜组织中的慢性感染结果在一系列因素释放中，诱导嗜中性粒细胞激活和从骨髓加速募集。这新兴的神经磷中的人群在被细菌激活后具有较高的患有Netosis的能力产品在受损的肠壁上泄漏。从激活的中性粒细胞释放的网促进 HIV-1感染中血管功能障碍的进展。总体目标将在三个中实现具体目的：1）确定嗜中性粒细胞激活和Netosis预测的程度 HIV-1感染者的血管功能障碍； 2）定义慢性全身性嗜中性粒细胞的机制 HIV-1感染激活； 3）定义与之相关的基于中性粒细胞的预后标记 HIV-1感染中与血管疾病相关的病态事件。我们希望拟议的项目从根本上提高我们对主要的理解 HIV-1感染中炎症驱动的血管疾病的机制。机制驾驶的定义 HIV-1感染者中血管疾病的进展将具有重大的翻译影响，并且作为新型诊断和治疗方法的基础。