Immune Cell Interactions in Atherosclerosis

动脉粥样硬化中的免疫细胞相互作用

• 批准号: 10334090
• 负责人: Catherine C Hedrick
• 金额: $ 28.97万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334090
• 关键词: Address; Angiography; Anti-Inflammatory Agents; Antigens; Apolipoproteins; Apolipoproteins B; Arterial Fatty Streak; Arteries; Atherosclerosis; B-Lymphocyte Subsets; B-Lymphocytes; Blood Vessels; CCR6 gene; CD8-Positive T-Lymphocytes; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Communication; Cell physiology; Cells; Cholesterol; Chronic; Clinical; Clinical Data; Clinical Trials; Colchicine; Complement; Coronary; Coronary Arteriosclerosis; Development; Disease; Dose; Enrollment; Epitopes; Event; Genetic Transcription; Goals; Host Defense; Human; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunoglobulin M; Impairment; Incidence; Infection; Inflammatory; Interleukin-1 beta; Intervention; Laboratories; Lead; Link; Lipids; Lipoproteins; Longitudinal cohort; Low-Density Lipoproteins; Lymphocyte; Lymphoid Tissue; Measures; Membrane Microdomains; Metabolic; Metabolism; Modeling; Molecular; Monoclonal Antibodies; Multi-Ethnic Study of Atherosclerosis; Mus; Myelogenous; Myeloid Cells; National Heart, Lung, and Blood Institute; Nature; Outcome; Outcome Study; Patients; Pattern; Peptide Sequence Determination; Peptides; Peripheral Blood Mononuclear Cell; Phase III Clinical Trials; Placebos; Plasma; Play; Production; Proteins; Reaction; Regulation; Research; Role; Seminal; Signal Transduction; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic immunosuppression; Thrombosis; Training; Universities; Virginia; Work; X-Ray Computed Tomography; adaptive immune response; atherogenesis; atheroprotective; base; cardiovascular risk factor; cohort; coronary plaque; cytokine; data sharing; disorder risk; follow-up; high dimensionality; human subject; immune function; immunoregulation; lymph nodes; macrophage; member; monocyte; mouse model; natural antibodies; novel therapeutic intervention; oxidized lipid; oxidized low density lipoprotein; prevent; programs; receptor; response; transcriptome sequencing

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.

总体抽象 我们的PPG将检验以下假设：脂蛋白的脂质和蛋白质成分引发先天和 控制人类动脉粥样硬化的自适应免疫复杂。我们将研究免疫细胞串扰 发生在人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），正如最近的临床试验清楚地表明的那样。但是，这些试验也告诉我们系统性 免疫系统的治疗本质上会损害宿主的防御。那是必须找到新的， 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，但备用宿主防御。我们 将研究来自3个良好特征临床队列的人类受试者的免疫细胞和血浆，1- 现有的Cava队列（弗吉尼亚州的冠状动脉评估），其中来自UVA心脏的受试者 进行定量冠状动脉分析的导管实验室； 2- 计算机断层扫描（CT）-Cava队列，受试者接受无创CT血管造影的受试者 将遵循PPG更新（基线措施）的第1年和第2年的心血管疾病评估 在3年时上升，以确定冠状斑块的进展和斑块标记的变化 脆弱性和3-动脉粥样硬化的多种族研究（MESA），这是一个大型NHLBI赞助的 自2000年以来一直在进行的纵向队列。在此协同程序中，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经确定了表达的新单核细胞子集 四跨果蛋白CD9，并将研究CD9如何影响单核细胞的新陈代谢和免疫调节 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将 研究专门的脂质筏信号传导如何驱动巨噬细胞中的转录和代谢重编程。 项目3调节鼠和人动脉粥样硬化中产生IgM的IgM B细胞将研究 新近鉴定的人B-1细胞亚群的CD24和CCR6如何调节动脉保护IgM的产生。 项目4 APOB特异性CD4和CD8 T细胞加剧动脉粥样硬化将识别和研究 免疫主导的人载脂蛋白B（APOB）表位以研究这些激活CD4和CD8 T 使用鼠标模型来解决机制的细胞。与我们的PPG的重要协同方面是它很高 互动，在该B细胞，T细胞，单核细胞和巨噬细胞在动脉壁中相互通信 在淋巴组织中。我们计划的独特方面是研究人类免疫细胞， 链接到来自3个完整心血管群的生物测量和临床数据，无偏见的使用 所有人类免疫细胞的单细胞水平上的尺寸蛋白和RNA顺序从相同 人类受试者，以及我们将所有小组发现与大量临床数据联系起来的能力 主题。人类研究由适用的鼠力学模型完成。结尾 我们的研究的目标是确定针对免疫细胞功能的安全新治疗策略以限制CAD。