The role of neutrophil recruitment in arterial diseases

中性粒细胞募集在动脉疾病中的作用

• 批准号: 8313874
• 负责人: YUQING HUO
• 金额: $ 17.85万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313874
• 关键词: Affect; Angioplasty; Antibodies; Apolipoprotein E; Area; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; Binding; Blood Platelets; Breeding; Cell Adhesion Molecules; Cells; Collagen; Development; Diet; Disease; Disease model; Endothelium; Enzymes; Evans blue stain; Genes; Glycoproteins; Goals; Golgi Apparatus; Homeostasis; Homing; Inflammatory; Injury; Knock-out; L-Selectin; Lead; Lesion; Leukocytes; Ligands; Link; Lipids; Lymphocyte; Measures; Mediating; Messenger RNA; Mononuclear; Mus; Natural regeneration; Neutrophil Infiltration; Nucleic Acid Regulatory Sequences; Outcome; P-Selectin; P-selectin ligand protein; Pathogenesis; Pathology; Peroxidases; Polysaccharides; Prevention approach; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Selectins; Smooth Muscle Myocytes; Staining method; Stains; Surface; T-Lymphocyte; Testing; Time; Transgenic Mice; arterial lesion; base; beta-1,3-Galactosyl-o-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase; expectation; feeding; glycosylation; injured; macrophage; monocyte; neutrophil; recombinase

DESCRIPTION: Lesions and neointima that forms following arterial injury are two of the major arterial pathologies in atherosclerosis. These two arterial pathologies are initiated by the recruitment of leukocytes to the arterial vessel walls. The long-term goal of this research is to determine the role of neutrophils in the genesis of arterial diseases. The central hypothesis of this proposal is that neutrophil recruitment to arterial vessel walls is required for the contribution of neutrophils to the development of arterial diseases. In contrast to the well-documented effect of mononuclear cells on the development of arterial diseases, especially spontaneous lesions, the involvement of neutrophils in these arterial diseases is disputable. However, one recent study has reported increased atherosclerosis in mice with a high neutrophil count and decreased atherosclerosis in mice treated with a neutrophil depletion antibody. Although that study points to an important role of neutrophils in atherosclerosis, the approaches it used alter neutrophil homeostasis, and it thus fails to establish a direct link between neutrophil recruitment to the arterial vessel wall and the development of arterial diseases under normal leukocyte homeostasis. Leukocyte recruitment to the arterial vessel wall is initiated by leukocyte tethering and rolling; the latter are mediated by leukocyte selectin ligands [PSGL-1 (ligand for P-selectin) and ligands for E- and L-selectin]. Glycosylation of selectin ligands is crucial for the binding of selectin ligands to the selectins. Core2 1-6-N- glucosaminyltransferase-I (C2GlcNAcT-I) is one of the enzymes that mediate the glycosylation of selectin ligands. Our previous studies have shown that knockout of C2GlcNAcT-I almost completely eliminates leukocyte recruitment to arterial vessel walls and suppresses the formation of spontaneous and neointimal lesions in mice. We have recently generated neutrophil-specific Cre transgenic mice, mice in which the expression of Cre recombinase and EGFP are driven by the regulatory region of the myeloperoxidase (MPO) gene (MPO-Cre mice). By breeding these MPO-Cre mice with floxed C2GlcNAcT-I mice, we have generated mice with C2GlcNAcT-I deficiency specifically in neutrophils. ApoE-/- mice lacking C2GlcNAcT-I specifically in neutrophils (Neu-C2GlcNAcT-I-/-/apoE-/- mice) were also generated. We have found that neutrophils in these mice fail to interact with the endothelium. The goal of this project is to use these mice to investigate the effect of neutrophil recruitment to arterial vessel walls on the formation of spontaneous atherosclerotic lesions and neointimal lesions. Specifically, in two arterial disease models we will examine whether neutrophil C2GlcNAcT- I deficiency affects the recruitment of monocytes and/or platelets to the arterial vessel wall, endothelial regeneration, the formation of spontaneous lesions and arterial neointima following arterial injury in apoE-/- mice. These studies will provide evidence that inhibition of neutrophil recruitment to arteries is a viable approach to the prevention and treatment of arterial diseases.

描述：动脉损伤后形成的病变和新内膜是动脉粥样硬化中的两个主要动脉病理。这两种动脉病理是通过将白细胞募集到动脉血管壁中引发的。这项研究的长期目标是确定中性粒细胞在动脉疾病起源中的作用。该提案的中心假设是，嗜中性粒细胞对中性粒细胞对动脉疾病的发展需要嗜中性粒细胞募集到动脉血管壁。与单核细胞对动脉疾病（尤其是自发性病变的发展）相比，中性粒细胞参与这些动脉疾病是有争议的。然而，一项最近的研究报告说，嗜中性粒细胞计数高的小鼠动脉粥样硬化增加，用中性粒细胞耗尽抗体治疗的小鼠动脉粥样硬化降低。尽管该研究指出了中性粒细胞在动脉粥样硬化中的重要作用，但它使用的方法改变了中性粒细胞稳态，因此未能在中性粒细胞募集到动脉血管壁与动脉疾病的发展与正常白细胞稳态下的动脉疾病的发展之间建立直接联系。 白细胞募集到动脉血管壁是由白细胞绑扎和滚动引发的。后者是由白细胞选择素配体[PSGL-1（P-Selectin的配体）和E-和L-链蛋白的配体介导的。选择素配体的糖基化对于选择素配体与Selectins的结合至关重要。 CORE2 1-6-N-葡萄糖氨基转移酶-I（C2GLCNACT-I）是介导选择素配体糖基化的酶之一。我们先前的研究表明，C2GLCNACT-I的敲除几乎完全消除了白细胞募集到动脉血管壁上，并抑制了小鼠自发性和新内膜病变的形成。我们最近产生了中性粒细胞特异性CRE转基因小鼠，其中CRE重组酶和EGFP的表达是由骨髓氧化酶（MPO）基因（MPO-CRE小鼠）的调节区域驱动的。通过用flox的C2GlcnAct-I小鼠繁殖这些MPO-CRE小鼠，我们在中性粒细胞中特异性地产生了具有C2GLCNACT-I缺乏症的小鼠。还会产生缺乏C2GLCNACT-I的APOE - / - 小鼠（neu-C2GlcNACT-I - / - / - /APOE-/ - 小鼠）。我们发现这些小鼠中的中性粒细胞无法与内皮相互作用。该项目的目的是使用这些小鼠研究中性粒细胞募集到动脉血管壁对自发动脉粥样硬化病变和新内膜病变形成的影响。具体而言，在两个动脉疾病模型中，我们将检查中性粒细胞C2GlcNACT-I缺乏是否会影响单核细胞和/或血小板募集到动脉血管壁，内皮再生，内皮再生，自发性病变和动脉新生症的组成和动脉新生症的组成。这些研究将提供证据表明，抑制中性粒细胞募集动脉是预防和治疗动脉疾病的可行方法。

项目成果

Glucose and Palmitate Differentially Regulate PFKFB3/iPFK2 and Inflammatory Responses in Mouse Intestinal Epithelial Cells.

• DOI: 10.1038/srep28963
• 发表时间: 2016-07-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Botchlett R;Li H;Guo X;Qi T;Zhao J;Zheng J;Woo SL;Pei Y;Liu M;Hu X;Chen G;Guo T;Yang S;Li Q;Xiao X;Huo Y;Wu C
• 通讯作者: Wu C

Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity.

• DOI: 10.1038/srep22612
• 发表时间: 2016-03-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Guo T;Woo SL;Guo X;Li H;Zheng J;Botchlett R;Liu M;Pei Y;Xu H;Cai Y;Zeng T;Chen L;Li X;Li Q;Xiao X;Huo Y;Wu C
• 通讯作者: Wu C

Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase.

• DOI: 10.1111/jnc.12463
• 发表时间: 2014-01
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Li R;Xie DD;Dong JH;Li H;Li KS;Su J;Chen LZ;Xu YF;Wang HM;Gong Z;Cui GY;Yu X;Wang K;Yao W;Xin T;Li MY;Xiao KH;An XF;Huo Y;Xu ZG;Sun JP;Pang Q
• 通讯作者: Pang Q

PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs.

• DOI: 10.1038/srep24324
• 发表时间: 2016-04-15
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chen L;Zhao J;Tang Q;Li H;Zhang C;Yu R;Zhao Y;Huo Y;Wu C
• 通讯作者: Wu C

Adenosine A1 Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms.

• DOI: 10.1167/iovs.15-17202
• 发表时间: 2015-12
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Shuya Zhang;Haiyan Li;Bo Li;Dingjuan Zhong;Xuejiao Gu;Lingyun Tang;Yanyan Wang;Cun Wang