Myeloid cell interactions in atherosclerosis

动脉粥样硬化中的骨髓细胞相互作用

• 批准号: 9311933
• 负责人: Klaus F. Ley
• 金额: $ 45万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311933
• 关键词: Address; Antigen Presentation; Aorta; Apolipoprotein E; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Behavior; Biological Models; Bromodeoxyuridine; Cell Communication; Cell Shape; Cells; Cessation of life; Characteristics; Color; Dancing; Data; Dendrites; Endothelial Cells; Endothelium; External carotid artery structure; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Hot Spot; ITGAM gene; Image; In Situ; Inflammation; Injectable; Integrin alpha4beta1; Integrins; Label; Leukocytes; Ligands; Measures; Methods; Microscopy; Minimally modified Low Density Lipoprotein; Modernization; Molecular; Molecular Profiling; Monoclonal Antibodies; Movement; Mus; Mutation; Myeloid Cells; Myocardial Infarction; Nature; Pattern; Peripheral arterial disease; Phenotype; Primary Prevention; Proliferating; Research; Secondary Prevention; Spottings; Stroke; Surface; Technology; Testing; Time; Work; base; cadherin 5; cell type; chemokine; chemokine receptor; deep sequencing; differential expression; experimental study; genome-wide; image processing; imaging system; in vivo; intravital microscopy; live cell imaging; macrophage; microscopic imaging; migration; monocyte; movie; oxidized low density lipoprotein; programs; tool; transcriptome; transcriptome sequencing; uptake

Description Although tremendous progress has been made in primary and secondary prevention, the complications of atherosclerosis (heart attacks, strokes and peripheral artery disease) still account for the most deaths worldwide. Here, we propose to test three hypotheses. This work has become possible through the intravital live cell triggered imaging system (ILTIS) we developed in the current funding cycle. Hypothesis 1 is that non- classical monocytes use LFA-1 (αLβ2 integrin) and ~40% also VLA-4 (α4β1 integrin) to patrol the endothelium overlying atherosclerotic plaque. We have preliminary evidence for at least two subsets of patrolling monocytes in atherosclerotic arteries. To test the molecular mechanism of patrolling, we will block integrins, their ligands, chemokines and chemokine receptors using monoclonal antibodies. Hypothesis 2 is that blood monocytes gain access to atherosclerotic plaque through the luminal endothelium. To test how monocytes enter atherosclerotic lesions, we have made mice with yellow (YFP) endothelium that are crossed into the Apoe-/- atherosclerosis- prone background. Combining these mice with mice in which monocyte subsets are fluorescently labeled (Cx3cr1GFP/+ for non-classical, Ccr2RFP/+ for classical monocytes) will show transendothelial migration of monocytes into atherosclerotic plaque in vivo. Hypothesis 3 is that four newly discovered plaque macrophage subsets (by ILTIS) have different functions. Preliminary RNA-Seq data show that their gene expression profiles vary significantly. We will test these functions: proliferation by BrdU and Ki67; oxLDL and minimally modified (mm)LDL uptake; efferocytosis; migration and antigen presentation. When the proposed work is complete, we will know, for the first time, how monocytes patrol atherosclerotic arteries, how they enter atherosclerotic lesions and what they do there. We will identify key functions of the four newly discovered monocyte and macrophage subsets in atherosclerotic plaque.

描述 尽管在预防初级和次要的预防中已经取得了巨大进展，但汇编的汇编 动脉粥样硬化（心脏病发作，中风和周围性抗疾病）仍然是死亡人数最多的 在世界范围内。 我们在当前的资金周期中开发的活细胞触发成像系统（ILTIS）。 经典的单核细胞使用LFA-1（αLβ2整合素）和〜40％的VLA-4（α4β1整合素）巡逻内皮 上覆盖的动植物斑块。 在动脉粥样硬化的动脉中。 使用单克隆抗体的趋化因子和趋化因子受体。 通过腔内皮细胞进入屈服斑块。 病变，我们已经用黄色（YFP）内皮变成了apoE - / - 动脉粥样硬化 - 俯卧的背景。 （对于非古典，CCR2RFP/+的CX3CR1GFP/+，用于经典单核细胞）将显示跨内皮迁移 单核细胞进入体内的动脉粥样硬化斑块。 子集（通过ILTIS）具有不同的功能。 我们将测试这些功能很大。 （MM）LDL摄取； 将首次知道单核细胞如何巡逻动脉粥样硬化动脉，如何进入动脉粥样硬化 病变，他们在那里做。 动脉粥样硬化斑块中的巨噬细胞子集。