Monocyte Subsets & Immunity in Mouse and Human Atherosclerosis

单核细胞亚群

• 批准号: 10188605
• 负责人: Catherine C Hedrick
• 金额: $ 39.68万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188605
• 关键词: Anti-Inflammatory Agents; Antigens; Apolipoprotein E; Apoptotic; Atherosclerosis; Biological Markers; Blood; Blood Vessels; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cause of Death; Cell Communication; Cell surface; Cells; Clinical Research; Cytometry; Development; Disease; Endothelium; Gender; Goals; Homeostasis; Human; Immune; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injury; Leukocytes; Link; Measures; Metals; Methods; Multi-Ethnic Study of Atherosclerosis; Mus; Myeloid Cells; Necrosis; Neoplasm Metastasis; Peripheral Blood Mononuclear Cell; Phenotype; Play; Proteins; Publishing; Reporting; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Site; Study Subject; Surveys; TLR7 gene; Testing; Tissues; Vascular Endothelium; antibody conjugate; atheroprotective; cardiovascular disorder risk; cardiovascular risk factor; cohort; coronary artery calcium; coronary calcium scoring; differential expression; ethnic difference; gender difference; high risk; human subject; innovation; macrophage; monocyte; neoplastic cell; oxidized low density lipoprotein; pathogen; preservation; receptor

Project 1 ABSTRACT Studies over the last decade have identified the presence of 3 subsets of blood monocytes. The three subsets are: classical or `inflammatory' monocytes, nonclassical or `patrolling' monocytes, and intermediate monocytes. Elevated numbers of classical monocytes are correlated with progression of human cardiovascular disease (CVD), but less is known about the functions of intermediate and nonclassical monocytes in human CVD. Many published clinical studies have lumped the nonclassical and intermediate human monocytes together, making it impossible to discern their unique functions. Thus, valid functions of these subsets in humans remain elusive. What is clear is that monocytes play key roles in human CVD and that individually targeting different monocyte subsets may modulate the immune-cell dysregulation that occurs in atherosclerosis. Triggering Receptor Expressed On Myeloid Cells-Like 4 (TREML4) is a receptor that is preferentially expressed on myeloid cells. TREML4 recognizes dying and necrotic cells, provides protective immunity, and is required for TLR7 signaling. We found that murine nonclassical monocytes have very high expression of TREML4. Interestingly, a single nucleotide polymorphism (SNP) in TREML4 has been linked with coronary artery calcium (CAC) in two human cohorts. Thus, we propose to study the impact of TREML4 on atherosclerosis progression. We hypothesize that TREML4 is anti-inflammatory and is increased in human and mouse monocytes during atherosclerosis progression to protect against inflammation. The goals of Project 1 are: 1) to test whether TREML4 is atheroprotective, 2) to identify functions of TREML4 on monocyte subsets in atherosclerosis, 3) to test whether TREML4+ monocytes in humans are functionally associated with cardiovascular disease, and 4) to identify how human monocytes are phenotypically and functionally changed in CVD. We will test our hypotheses in the following aims: Specific Aim 1 will test whether TREML4 is atheroprotective. Specific Aim 2 will test how a single nucleotide polymorphism (rs2803496) in human TREML4 known to be linked to CAC functionally changes human monocyte subsets, and how TREML4 is linked to CVD in humans. We will study subjects in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who have CAC scores =0 (low risk CVD) or >300 (high risk CVD). At the conclusion of our studies, we will know the function of TREML4 in atherosclerosis and if TREML4 is a new biomarker for CAC levels and CVD risk. We will know how human monocytes change during cardiovascular disease, if there are ethnic-specific or gender-specific monocyte changes, and we will have identified new targets for regulating human monocyte subset function in CVD.

项目 1 摘要 过去十年的研究已确定存在 3 个血液单核细胞亚群。三个 子集是：经典或“炎症”单核细胞、非经典或“巡逻”单核细胞，以及 中间单核细胞。经典单核细胞数量的增加与疾病的进展相关 人类心血管疾病（CVD），但人们对中间体和中间体的功能知之甚少。 人类心血管疾病中的非经典单核细胞。许多已发表的临床研究都将非经典疗法归为一类 和中间人类单核细胞在一起，使得无法辨别它们独特的功能。 因此，这些子集在人类中的有效功能仍然难以捉摸。很明显，单核细胞发挥作用 在人类 CVD 中发挥关键作用，单独针对不同的单核细胞亚群可能会调节 动脉粥样硬化中发生的免疫细胞失调。骨髓表达的触发受体 Cells-Like 4 (TREML4) 是一种优先在骨髓细胞上表达的受体。特雷姆4 识别垂死和坏死的细胞，提供保护性免疫，并且是 TLR7 信号传导所必需的。我们 发现小鼠非经典单核细胞具有非常高的 TREML4 表达。有趣的是，单个 TREML4 中的核苷酸多态性 (SNP) 与两种疾病中的冠状动脉钙 (CAC) 相关 人类群体。因此，我们建议研究 TREML4 对动脉粥样硬化进展的影响。我们 假设 TREML4 具有抗炎作用，并且在人类和小鼠单核细胞中增加 动脉粥样硬化进展以防止炎症。项目 1 的目标是：1）测试是否 TREML4 具有动脉粥样硬化保护作用，2) 鉴定 TREML4 对动脉粥样硬化中单核细胞亚群的功能， 3) 测试人类TREML4+单核细胞是否与心血管功能相关 疾病，4) 确定人类单核细胞在 CVD 中如何发生表型和功能变化。 我们将在以下目标中测试我们的假设： 具体目标 1 将测试 TREML4 是否是 动脉粥样硬化保护。具体目标 2 将测试人类中的单核苷酸多态性 (rs2803496) 已知与 CAC 相关的 TREML4 在功能上改变人类单核细胞亚群，以及 TREML4 如何改变人类单核细胞亚群 与人类 CVD 相关。我们将研究动脉粥样硬化多种族研究 (MESA) 中的受试者 CAC 评分 = 0（低风险 CVD）或 > 300（高风险 CVD）的队列。在我们的结论中 研究，我们将了解 TREML4 在动脉粥样硬化中的功能，以及 TREML4 是否是动脉粥样硬化的新生物标志物 CAC 水平和 CVD 风险。我们就会知道人类单核细胞在心血管疾病期间如何变化，如果 存在种族特异性或性别特异性的单核细胞变化，我们将确定新的目标 用于调节 CVD 中的人类单核细胞亚群功能。