Immune Cell Interactions in Atherosclerosis

总体摘要 我们的PPG将测试这一假设，即脂蛋白的脂和蛋白质成分触发先天和 控制人类动脉粥样硬化的适应性免疫反应。我们将研究免疫细胞间的相互作用 发生在人类动脉粥样硬化进展过程中。免疫在冠状动脉疾病中起着重要作用 (CAD)，正如最近的临床试验清楚地证明的那样。然而，这些试验也告诉我们，系统性的 免疫系统的治疗，就其本质而言，会削弱宿主防御。因此，必须找到新的， 在动脉粥样硬化中调节免疫细胞功能的更具体的干预措施，而不是宿主防御。我们 将研究来自3个有良好特征的临床队列的人类受试者的免疫细胞和血浆，1-OUR 现有CAVA队列(弗吉尼亚州冠状动脉评估)，受试者来自UVA心脏 接受冠状动脉定量分析以量化疾病的导管室；2- 计算机断层扫描(CT)-腔静脉队列，接受无创性CT血管成像的受试者 将遵循PPG续展的第一年和第二年的心血管疾病评估(基线措施) 最长3年，以确定冠状动脉斑块进展和斑块标记物的变化 脆弱性，以及3--由NHLBI赞助的大型动脉粥样硬化多种族研究(MESA) 自2000年以来一直在进行的纵向队列。在这个协同计划中，项目1 CD9+单核细胞 动脉粥样硬化中的巨噬细胞免疫功能已发现新的单核细胞亚群表达 并将研究CD9如何影响单核细胞的新陈代谢和免疫调节 冠心病中的巨噬细胞。项目2动脉粥样硬化中炎性巨噬细胞的胆固醇调节将 研究专门的脂筏信号如何驱动巨噬细胞的转录和代谢重编程。 项目3将研究小鼠和人类动脉粥样硬化中产生免疫球蛋白M的B细胞对动脉粥样硬化的保护作用 新发现的人类B-1细胞亚群上的CD24和CCR6如何调节抗动脉粥样硬化的IgM的产生。 项目4将识别和研究ApoB特异的CD4和CD8 T细胞加剧动脉粥样硬化 免疫优势的人载脂蛋白B(ApoB)表位研究它们如何激活CD4和CD8T 细胞使用鼠标模型来解决机制。我们PPG的一个重要的协同方面是它高度 在动脉壁中，B细胞、T细胞、单核细胞和巨噬细胞相互通信 在淋巴组织中。我们项目的独特之处在于专注于研究人类免疫细胞， 链接到生物样品和来自3个互补心血管队列的临床数据，使用无偏高 来自同一来源的所有人类免疫细胞在单细胞水平上的三维蛋白质和RNA测序 人类受试者，以及我们将我们团队的所有发现与每个项目的大量临床数据联系起来的能力 主题。在适用的情况下，人类研究得到了小鼠机制模型的补充。结束 我们研究的目标是找到针对免疫细胞功能的安全新的治疗策略，以限制CAD。

Overall Abstract Our PPG will test the hypothesis that the lipid and protein components of lipoproteins trigger innate and adaptive immune responses that control human atherosclerosis. We will study the immune cell cross-talk that occurs during human atherosclerosis progression. Immunity plays an important role in coronary artery disease (CAD), as recent clinical trials have clearly demonstrated. However, these trials also taught us that systemic treatments of the immune system, by their very nature, impair host defense. Thus, it is imperative to find new, more specific interventions that modulate immune cell function in atherosclerosis, yet spare host defense. We will study immune cells and plasma from human subjects from 3 well-characterized clinical cohorts, 1-our existing CAVA cohort (Coronary Assessment at Virginia), where subjects are enrolled from the UVA cardiac catheterization laboratory that undergo quantitative coronary analysis for disease quantification; 2- Computerized Tomography (CT)-CAVA cohort, where subjects undergoing noninvasive CT angiography for cardiovascular disease assessment in years 1 and 2 of the PPG renewal (baseline measures) will be followed up at 3 years to allow for determination of coronary plaque progression and changes in markers of plaque vulnerability, and 3- The Multi-Ethnic Study of Atherosclerosis (MESA), a large NHLBI-sponsored longitudinal cohort that has been ongoing since 2000. In this synergistic program, Project 1 CD9+ Monocyte and Macrophage Immune Functions in Atherosclerosis has identified new monocyte subsets expressing the tetraspanin CD9, and will study how CD9 impacts metabolism and immune modulation of monocytes and macrophages in CAD. Project 2 Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis will study how specialized lipid raft signaling drives transcriptional and metabolic reprogramming in macrophages. Project 3 Regulation of Atheroprotective IgM-producing B cells in Murine and Human Atherosclerosis will study how CD24 and CCR6 on newly identified human B-1 cell subsets modulate atheroprotective IgM production. Project 4 ApoB-Specific CD4 and CD8 T cells Exacerbate Atherosclerosis will identify and study immunodominant human apolipoprotein B (apoB) epitopes to investigate how these activate CD4 and CD8 T cell using mouse models to address mechanisms. An important synergistic aspect to our PPG is that it is highly interactive, in that B cells, T cells, monocytes and macrophages communicate with each other in the artery wall and in lymphoid tissues. Unique aspects of our program are the focus on studying human immune cells, the link to biospecimens and clinical data from 3 complementary cardiovascular cohorts, the use of unbiased high dimensional protein and RNA-sequencing at the single cell level for all human immune cells from the same human subjects, and our ability to link all of our group’s discoveries with extensive clinical data on each subject. The human studies are complemented by murine mechanistic models where applicable. The end goal of our studies is to identify safe new therapeutic strategies targeting immune cell function to limit CAD.