Immune Cell Interactions in Atherosclerosis

摘要 在过去的十年里，包括我们自己在内的几个研究小组已经表明了免疫细胞亚群的重要性 但是我们才刚刚开始发现免疫细胞是如何代谢的， 人类动脉粥样硬化形成期间转录发生变化。该PPG将专注于人类心血管 疾病，并将测试假设，脂蛋白与其脂质和蛋白质成分触发先天性和 影响动脉粥样硬化的适应性免疫反应。我们将研究免疫细胞的功能变化， 在人类动脉粥样硬化进展过程中发生的免疫细胞串扰， 表征NHLBI申办的纵向临床队列，动脉粥样硬化多种族研究（梅萨），以及 我们的UVA心血管队列。我们将研究心血管风险低与高的受试者， 冠状动脉钙化（CAC）Agatston评分。CAC Agatston评分具有较高的阳性预测 心血管疾病（CAD）事件的数值和Agatston评分（300分以上）是心血管疾病（CAD）事件的强预测因子。 未来的CAD活动。我们将研究CAC Agatston评分>300的受试者作为高风险， 按年龄和性别匹配的对照组，Agatston评分为0为低风险。在这个协同方案中， 项目1单核细胞亚群&小鼠和人类动脉粥样硬化的免疫，将研究单核细胞如何 亚群对氧化低密度脂蛋白的反应影响心血管疾病。项目2胆固醇调节 动脉粥样硬化中的炎症巨噬细胞，将研究胆固醇如何调节巨噬细胞 动脉粥样硬化中的极化。项目3小鼠和人类动脉粥样硬化中的B细胞亚群，将研究如何 特异性趋化因子受体促进B细胞亚群迁移和动脉粥样硬化保护。项目4 ApoB特异性 小鼠和人动脉粥样硬化中的CD 4 T细胞，将检验apoB特异性CD 4 T细胞是 通过产生IL-10来保护动脉粥样硬化，但在疾病后期失效。我们PPG的一个重要协同方面是， B细胞、T细胞、单核细胞和巨噬细胞在动脉壁和淋巴管中相互交流。 每个项目都研究这些免疫细胞亚群中的一个，因此有许多项目相互作用。 我们的计划的独特之处是对研究人类免疫细胞的强烈关注，使用CyTOF质量 细胞计量术和RNA-Seq作为用于研究这些细胞的创新方法， 免疫球蛋白使用ELISA为基础的测定在我们的小组开发，目前用于多个临床 试验，以及我们将我们小组的所有发现与15年广泛的梅萨临床数据库联系起来的能力， 了解免疫细胞如何改变以促进CAC进展和心血管疾病。年底 我们的研究目标是确定新的治疗策略，靶向免疫细胞功能，以限制 心血管疾病

ABSTRACT In the past decade, several groups, including our own, have shown the importance of immune cell subsets on atherogenesis in mice, but we are just beginning to discover how immune cells are metabolically and transcriptionally changed during atherogenesis in humans. This PPG will focus on human cardiovascular disease, and will test the hypothesis that lipoproteins with their lipid and protein components trigger innate and adaptive immune responses that impact atherosclerosis. We will study functional changes in immune cells and the immune cell cross-talk that occurs during atherosclerosis progression in humans using the well- characterized NHLBI-sponsored longitudinal clinical cohort, Multi-Ethnic Study of Atherosclerosis (MESA), and our UVA Cardiovascular Cohort. We will study subjects who have low versus high cardiovascular risk based on their coronary artery calcium (CAC) Agatston scores. CAC Agatston scores have high positive predictive values for cardiovascular disease (CAD) events, and Agatston scores (above 300) are strong predictors of future CAD events. We will study subjects with CAC Agatston scores >300 as high risk, and we have carefully matched controls by age and gender with Agatston scores of zero as low risk. In this synergistic program, Project 1 Monocyte Subsets & Immunity in Mouse and Human Atherosclerosis, will study how monocyte subsets respond to oxidized LDL to impact cardiovascular disease. Project 2 Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis, will investigate how cholesterol modulates macrophage polarization in atherosclerosis. Project 3 B Cell Subsets in Mouse and Human Atherosclerosis, will study how specific chemokine receptors promote B cell subset migration and atheroprotection. Project 4 ApoB-Specific CD4 T cells in Mouse and Human Atherosclerosis, will test the hypothesis that apoB-specific CD4 T cells are atheroprotective by producing IL-10, but fail later in disease. An important synergistic aspect to our PPG is that B cells, T cells, monocytes and macrophages communicate with each other in the artery wall and lymphoid tissues, and each project studies one of these immune cell subsets, so there are many project interactions. Unique aspects of our program are the strong focus on studying human immune cells, the use of CyTOF mass cytometry and RNA-Seq as innovative methodologies used to study these cells, the measurement of plasma immunoglobulins using ELISA-based assays developed in our group and currently used in multiple clinical trials, and our ability to link all of our group's discoveries with a 15-year extensive MESA clinical database to understand how immune cells change to contribute to CAC progression and cardiovascular disease. The end goal of our studies is to identify novel therapeutic strategies targeting immune cell function to limit cardiovascular disease.