Dissecting the cellular and molecular immune interactions in human atherosclerosis

剖析人类动脉粥样硬化中的细胞和分子免疫相互作用

基本信息

批准号：
9227033
负责人：
Chiara Giannarelli
金额：
$ 8.48万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9227033
关键词：
Anti-Inflammatory Agents Anti-inflammatory Arterial Fatty Streak Atherosclerosis Blood CCL2 gene CREB1 gene CXCL1 gene CXCL10 gene Cardiovascular Diseases Cardiovascular system Carotid Artery Diseases Cells Characteristics Chronic Clinical Clinical Data Clinical Research Complex Computer Analysis Cytometry Data Disease EGF gene Enrollment Event Gene Expression Profile Genes Goals Human Immune Immune Sera Immune response Immune system Inflammation Interferons Knowledge Ligands Lipids MAPK14 gene Measures Molecular Molecular Profiling Molecular Target Morbidity - disease rate Operative Surgical Procedures Patients Peripheral Blood Mononuclear Cell Phenotype Plasma Platelet-Derived Growth Factor Processed Genes Production Public Health RNA RNA Processing RNA analysis Randomized Clinical Trials Regimen Residual state Role Sampling Signal Pathway Site Staging Stroke Systems Biology Techniques Technology Testing Tissues Transient Ischemic Attack Variant Virus Diseases clinical phenotype cytokine dimensional analysis disability immune activation improved innovative technologies mortality next generation next generation sequencing novel platelet-derived growth factor BB response standard of care

项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) due to atherosclerosis is the leading cause of mortality and disability globally. Even in patients treated with optimized standard-of-care regimens, residual morbidity and mortality remain high. New strategies that directly target atherosclerosis—the main cause of CVD—are urgently needed. Although recent conceptual advances have emphasized the importance of chronic inflammation and immune system activation in atherosclerosis in CVD, new promising anti-inflammatory agents tested in randomized clinical trials showed no benefits in either reducing cardiovascular end points or atherosclerotic plaque burden. The immune system is composed of a hierarchically organized set of molecular and cellular networks that act in concert in tissues and systemically. Yet, most studies of the role of immune system in atherosclerosis in humans have focused on circulating cells—with little or no focus on cellular immune infiltrates at the tissue site or the relationship between them. To gain a better understanding of systemic and local immune networks that contribute to CVD, we will take advantage of technological advances in molecular systems biology. Using CyTOF mass cytometry—a cutting-edge technique for high-dimensional analysis of immune cells—we identified single-cell variation and molecular activation of circulating peripheral blood mononuclear cells (PBMCs) and atherosclerotic tissue-associated immune cells in patients with carotid artery disease undergoing surgical revascularization. We will use a multi-tissue, systems biology approach to infer arterial wall- and blood-specific immune networks that govern the immune response at different stages of atherosclerosis. We will combine the use of innovative technologies such as CyTOF and RNA next-generation (NGS) to identify immune regulatory network relevant to human CVD disease. In specific Aim 1, we will identify the single-cell composition and molecular state of circulating and tissue-associated human immune cells. We will also determine the molecular and cellular correlates between systemic and tissue immune cell diversity and atherosclerotic and clinical phenotypes. In Specific Aim 2, we will identify immune networks in atherosclerosis and the clinical correlates of identified immune networks activated in atherosclerosis. The use of systems biology studies that integrate cutting-edge technologies to measure immune cell variation in patient samples to infer immune regulatory networks will deepen our knowledge of the contribution of the immune system to CVD and will set the stage to the selection of molecular targets for novel anti-inflammatory therapies.

项目摘要由于动脉粥样硬化而引起的心血管疾病（CVD）是死亡率和全球残疾。即使在接受优化标准治疗方案治疗的患者中，残留发病率和死亡率仍然很高。直接针对动脉粥样硬化的新策略 - CVD的主要原因 - 迫切需要。虽然最近的概念进步已经强调了慢性感染和免疫系统激活在 CVD中的动脉粥样硬化，在随机临床中测试的新承诺的抗炎剂试验显示，减少心血管终点或动脉粥样硬化斑块没有好处负担。免疫系统由一组分层组织的分子和蜂窝网络在组织中和系统地进行。然而，大多数关于作用的研究人类动脉粥样硬化中的免疫系统集中在循环细胞上，几乎没有或没有专注于组织部位的细胞免疫浸润或它们之间的关系。获得一个更好地了解有助于CVD的系统和局部免疫网络，我们将利用分子系统生物学的技术进步。使用细胞质量细胞仪 - 一种用于免疫细胞高维分析的尖端技术 - 我们鉴定的单细胞变异和循环外周血的分子激活一单核细胞（PBMC）和动脉粥样硬化组织相关的免疫小球患者颈动脉疾病接受手术血运重建。我们将使用多组织的系统推断动脉壁和血液特异性免疫网络的生物学方法在动脉粥样硬化的不同阶段的免疫反应。我们将结合创新的使用诸如Cytof和RNA下一代（NGS）等技术以识别免疫调节与人类CVD疾病有关的网络。在特定目标1中，我们将确定单细胞循环和组织相关的人类免疫细胞的组成和分子状态。我们还将确定全身和组织免疫之间的分子和细胞相关细胞多样性以及动脉粥样硬化和临床表型。在特定目标2中，我们将确定动脉粥样硬化中的免疫网络和已识别的免疫网络的临床相关性在动脉粥样硬化中激活。使用系统生物学研究的使用，以整合尖端测量患者样品中免疫细胞变异以推断免疫细胞调节的技术网络将加深我们对免疫系统对CVD的贡献的了解，并将为新型抗炎疗法的分子靶标选择了阶段。