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小组已经证明了免疫细胞亚群的重要性 但我们才刚刚开始发现免疫细胞是如何代谢和 在人类动脉粥样硬化形成过程中发生转录变化。这个PPG将专注于人类心血管疾病 疾病，并将检验假设，即脂蛋白及其脂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和 在人类动脉粥样硬化进展过程中发生的免疫细胞串扰 NHLBI赞助的纵向临床队列、动脉粥样硬化的多种族研究(MESA)，以及 我们的UVA心血管队列。我们将研究心血管风险低和高的受试者 他们的冠状动脉钙化(CAC)Agatston评分。CAC阿加特斯顿评分具有很高的积极预测性 心血管疾病(CAD)事件的值和Agatston评分(300以上)是很强的预测因子 未来的CAD活动。我们将研究CAC Agatston评分为300分的高风险科目，我们已经仔细地 根据年龄和性别匹配对照组，Agatston得分为0为低风险。在这个协同计划中， 项目1小鼠和人类动脉粥样硬化中的单核细胞亚群和免疫，将研究单核细胞如何 亚群对氧化的低密度脂蛋白产生反应，从而影响心血管疾病。项目2胆固醇调节 动脉粥样硬化中的炎性巨噬细胞，将研究胆固醇如何调节巨噬细胞 动脉粥样硬化中的极化。在小鼠和人类动脉粥样硬化中的B细胞亚群项目将研究如何 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。特定于ApoB的项目4 小鼠和人类动脉粥样硬化中的CD4T细胞，将检验载脂蛋白B特异性CD4T细胞是 通过产生IL-10来保护动脉粥样硬化，但在以后的疾病中失败。我们PPG的一个重要的协同方面是 B细胞、T细胞、单核细胞和巨噬细胞在动脉壁和淋巴样组织中相互联系 组织，每个项目都研究这些免疫细胞亚群中的一个，所以有许多项目相互作用。 我们项目的独特之处在于，我们非常注重研究人类免疫细胞，使用细胞TOF MASS 细胞术和RNA-Seq作为研究这些细胞的创新方法，测量了血浆 免疫球蛋白是由我们团队开发的，目前用于多个临床 试验，以及我们将我们团队的所有发现与15年来广泛的MESA临床数据库联系起来的能力 了解免疫细胞如何变化对CAC进展和心血管疾病做出贡献。结束 我们研究的目标是找出针对免疫细胞功能的新治疗策略，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.