Monocyte Subsets & Immunity in Mouse and Human Atherosclerosis

项目1 过去十年的研究已经确定了血液单核细胞的3个子集的存在。三 亚群是：经典或“炎性”单核细胞，非经典或“巡逻”单核细胞，和 中间单核细胞。经典单核细胞数量的升高与以下疾病的进展相关： 人心血管疾病（CVD），但了解较少的中间和 人CVD中的非经典单核细胞。许多已发表的临床研究将非经典 和中间的人单核细胞在一起，使得不可能辨别它们的独特功能。 因此，这些亚群在人类中的有效功能仍然难以捉摸。很清楚的是单核细胞 在人CVD中的关键作用，并且单独靶向不同的单核细胞亚群可以调节 动脉粥样硬化中发生的免疫细胞失调。髓样细胞上表达的触发受体 细胞样4（TREML4）是优先在骨髓细胞上表达的受体。TREML4 识别死亡和坏死细胞，提供保护性免疫，并为TLR7信号传导所需。我们 发现鼠非经典单核细胞具有非常高的TREML4表达。有趣的是，一个 TREML4的一个核苷酸多态性（SNP）与冠状动脉钙（CAC）有关， 人类队列因此，我们建议研究TREML4对动脉粥样硬化进展的影响。我们 假设TREML4是抗炎性的，并且在人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 TREML 4是动脉粥样硬化保护性的，2）鉴定TREML 4在动脉粥样硬化中对单核细胞亚群的功能， 3)为了测试人类中的TREML4+单核细胞是否与心血管疾病功能相关， 疾病，以及4）鉴定人单核细胞在CVD中如何表型和功能改变。 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 抗动脉粥样硬化的具体目标2将测试人类单核苷酸多态性（rs2803496） 已知与CAC相关的TREML 4在功能上改变人单核细胞亚群，以及TREML 4如何改变人单核细胞亚群。 与人类的心血管疾病有关我们将研究多种族动脉粥样硬化研究（梅萨）的主题 CAC评分=0（低风险CVD）或>300（高风险CVD）的队列。在结束我们的 研究，我们将知道TREML4在动脉粥样硬化中的功能，如果TREML4是一种新的生物标志物， CAC水平和CVD风险。我们将知道人类单核细胞在心血管疾病期间如何变化，如果 有种族特异性或性别特异性单核细胞的变化，我们将确定新的目标， 用于调节CVD中的人单核细胞亚群功能。

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.