Immune Cell Interactions in Atherosclerosis

总体摘要 我们的PPG将检验脂蛋白的脂质和蛋白质成分触发先天性和 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重要作用 (CAD)最近的临床试验已经清楚地证明。然而，这些试验也告诉我们， 免疫系统的治疗，就其本质而言，损害了宿主的防御。因此，当务之急是找到新的， 更具体的干预措施，调节免疫细胞功能的动脉粥样硬化，但备用主机防御。我们 将研究来自3个充分表征的临床队列（1-我们的 现有CAVA队列（弗吉尼亚州冠状动脉评估），其中受试者从UVA心脏 进行定量冠状动脉分析以进行疾病量化的导管插入实验室; 2- 计算机断层扫描（CT）-CAVA队列，受试者接受无创CT血管造影， 将随访PPG更新第1年和第2年的心血管疾病评估（基线测量） 最多3年，以确定冠状动脉斑块进展和斑块标志物的变化 脆弱性，和3-动脉粥样硬化的多种族研究（梅萨），一个大型的NHLBI赞助 自2000年以来一直在进行的纵向队列研究。在这个协同项目中，项目1 CD 9+单核细胞 和巨噬细胞免疫功能在动脉粥样硬化已经确定了新的单核细胞亚群表达 四跨膜蛋白CD 9，并将研究CD 9如何影响单核细胞的代谢和免疫调节， CAD中的巨噬细胞。项目2动脉粥样硬化中炎症性巨噬细胞的胆固醇调节 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研究小鼠和人类动脉粥样硬化中产生抗动脉粥样硬化IgM的B细胞的调节 新鉴定的人B-1细胞亚群上的CD 24和CCR 6如何调节抗动脉粥样硬化IgM的产生。 项目4 ApoB特异性CD 4和CD 8 T细胞急性动脉粥样硬化将识别和研究 免疫显性人载脂蛋白B（apoB）表位，以研究这些表位如何激活CD 4和CD 8 T 细胞使用小鼠模型来解决机制。我们PPG的一个重要协同方面是， 相互作用，在B细胞中，T细胞、单核细胞和巨噬细胞在动脉壁中相互沟通 和淋巴组织中。我们计划的独特之处是专注于研究人类免疫细胞， 链接到来自3个互补心血管队列的生物样本和临床数据，使用无偏高 在单细胞水平上对来自相同细胞的所有人免疫细胞进行三维蛋白质和RNA测序， 人类受试者，以及我们将我们小组的所有发现与每个人的广泛临床数据联系起来的能力。 话题吧在适用的情况下，通过鼠机制模型补充人体研究。年底 我们研究的目的是确定安全的新的治疗策略，靶向免疫细胞功能，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.