Immune Cell Interactions in Atherosclerosis

动脉粥样硬化中的免疫细胞相互作用

基本信息

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
项目类别：
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

项目摘要

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.

总体摘要我们的 PPG 将测试脂蛋白的脂质和蛋白质成分触发先天和我们将研究控制人类动脉粥样硬化的适应性免疫反应。免疫在人类动脉粥样硬化进展过程中发挥着重要作用。（CAD），正如最近的临床试验所清楚证明的那样，但是，这些试验也告诉我们系统性的。免疫系统的治疗本质上会损害宿主的防御能力，因此，必须找到新的、更有效的方法。我们可以采取更具体的干预措施来调节动脉粥样硬化中的免疫细胞功能，同时避免宿主防御。将研究来自 3 个特征明确的临床队列的人类受试者的免疫细胞和血浆，其中 1 个是我们的现有的 CAVA 队列（弗吉尼亚冠状动脉评估），其中受试者是从 UVA 心脏病入组进行定量冠状动脉分析以进行疾病量化的导管实验室；计算机断层扫描 (CT)-CAVA 队列，其中受试者接受无创 CT 血管造影将遵循 PPG 更新的第一年和第二年的心血管疾病评估（基线措施）最多 3 年，可确定冠状动脉斑块进展和斑块标记物的变化 3- 动脉粥样硬化多种族研究 (MESA)，一项由 NHLBI 赞助的大型项目自 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和巨噬细胞免疫功能已鉴定出表达四跨膜蛋白 CD9，并将研究 CD9 如何影响单核细胞和免疫调节 CAD 中的巨噬细胞项目 2 动脉粥样硬化中炎症巨噬细胞的胆固醇调节研究专门的脂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 将研究小鼠和人类动脉粥样硬化中产生动脉粥样硬化 IgM 的 B 细胞的调节新鉴定的人类 B-1 细胞亚群上的 CD24 和 CCR6 如何调节动脉粥样硬化 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鉴定和研究免疫显性人载脂蛋白 B (apoB) 表位，以研究它们如何激活 CD4 和 CD8 T 我们的 PPG 的一个重要的协同方面是它具有高度的协同作用。相互作用，B 细胞、T 细胞、单核细胞和巨噬细胞在动脉壁中相互通讯我们项目的独特之处在于研究人类免疫细胞，即链接到来自 3 个互补心血管队列的生物样本和临床数据，使用无偏高对来自同一细胞的所有人类免疫细胞进行单细胞水平的三维蛋白质和 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研究的广泛临床数据联系起来的能力在适用的情况下，人类研究得到了小鼠机制模型的补充。我们研究的目标是确定针对免疫细胞功能以限制 CAD 的安全新治疗策略。