The role of adenosine kinase in atherosclerosis

腺苷激酶在动脉粥样硬化中的作用

基本信息

批准号：
8764729
负责人：
YUQING HUO
金额：
$ 37.15万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764729
关键词：
ADORA2A gene ATP binding cassette transporter 1 Adenosine Adenosine Kinase Adhesiveness Adverse effects Affect Animal Model Animals Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Binding Biological Assay Blood Vessels Bone Marrow Cells CD36 gene Cell Adhesion Molecules Cells Chronic Development Disease Down-Regulation Endothelial Cells Endothelium Enzymes Foam Cells Goals Growth Half-Life Homing In Vitro Inflammation Inflammatory Inflammatory Response Lesion Leukocytes Ligands Lipids Macrophage Activation Messenger RNA Mus Myelogenous Myeloid Cells Pathway interactions Phosphorylation Physiology Play Prevention Process Production Proteins Purine Nucleosides Purinergic P1 Receptors Regulation Research Project Grants Role Signal Transduction Site Testing Therapeutic Agents Tissues Transplantation analog base chemokine chemokine receptor cytokine design evidence base extracellular feeding genetic approach in vitro Assay inhibitor/antagonist kinase inhibitor macrophage migration monocyte neovascularization novel novel strategies prevent research study response uptake vasa vasorum western diet

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall that progresses from a fatty streak to a fibrofattymatrix and fibrous plaque. Monocyte interactions with the inflamed endothelium, monocyte recruitment to the arterial vesselwall and their subsequent transformation to lipid-enriched foam cells initiate and sustain atherosclerosis. The long-term goal of this research project is to elucidate the mechanisms underlying the regulation of the inflammatory aspects of atherosclerosis so that novel evidence-based approaches can be developed to treat atherosclerosis. The central hypothesis of this proposal is that suppressing adenosine kinase (ADK) inhibits the inflammatory aspects of atherosclerosis and further curbs the formation of atherosclerotic lesions. Adenosine, a purine nucleoside that is elaborated the sites of inflammation, has a central role in regulating the inflammatory response. However, the short half-life and systemic side effects of adenosine or adenosine analogues limit their application. ADK is an intracellular enzyme that catalyzes the phosphorylation of adenosine to AMP. Inhibition of ADK increases the levels of adenosine in the intracellular compartment and causes a subsequent increase in the extracellular compartment. ADK inhibition is efficacious at suppressing many inflammatory diseases in animal models. However, the role of ADK inhibition in atherosclerosis has not been defined. We have recently found the following: (i) an ADK inhibitor suppresses the formation of atherosclerotic lesions in mice; (ii) ADK knockdown in endothelial cells decreases cytokine-induced endothelial activation; and (iii) the deficiency of ADK in myeloid leukocytes reduces the formation of atherosclerotic lesions in mice. The goal of this project is to use tissue- specific ADK-deficient mice to investigate the extent to which ADK deficiency in endothelial cells or monocytes/macrophages contributes to the reduction of inflammatory responses and the suppression of atherosclerosis. In specific aim 1, we will investigate the effect of endothelial ADK deficiency on the decreased inflammatory adhesiveness of the arterial endothelium and the suppressed formation of atherosclerotic lesions. In specific aims 2 to 4, we will investigate the effects of monocyte ADK deficiency on the decline of monocyte recruitment to atherosclerotic arteries, macrophage activation and foam cell formation, as well as the growth of advanced atherosclerotic lesions. We will also determine the contribution of the PI3K/Akt and adenosine receptor 2A (A2AR) to the effects of ADK deficiency. These studies will have significant implications for the use of ADK inhibitors as therapeutic agents to prevent and treat atherosclerosis and its complications.

描述（由申请人提供）：动脉粥样硬化是动脉血管壁的慢性炎症性疾病，从脂肪条纹发展为纤维状脂质肿瘤和纤维斑块。单核细胞与发炎的内皮，单核细胞募集到动脉容器壁的相互作用以及随后转化为富含脂质的富含脂质的泡沫细胞的转化，并维持动脉粥样硬化。该研究项目的长期目标是阐明调节动脉粥样硬化炎症方面的机制，以便可以开发出新颖的基于证据的方法来治疗动脉粥样硬化。该提议的中心假设是抑制腺苷激酶（ADK）抑制了动脉粥样硬化的炎症方面，并进一步遏制了动脉粥样硬化病变的形成。腺苷是一种阐明炎症部位的嘌呤核苷，在调节炎症反应中具有核心作用。但是，腺苷或腺苷类似物的半衰期和全身副作用限制了它们的应用。 ADK是一种细胞内酶，可催化腺苷对AMP的磷酸化。 ADK的抑制会增加细胞内室中腺苷的水平，并导致细胞外室的随后增加。 ADK抑制作用可有效抑制动物模型中的许多炎症性疾病。但是，尚未定义ADK抑制在动脉粥样硬化中的作用。我们最近发现了以下内容：（i）ADK抑制剂抑制小鼠动脉粥样硬化病变的形成；（ii）内皮细胞中的ADK敲低降低了细胞因子诱导的内皮激活；（iii）ADK在髓样白细胞中的缺乏减少了小鼠动脉粥样硬化病变的形成。该项目的目的是使用组织特异性ADK缺乏小鼠来研究内皮细胞或单核细胞/巨噬细胞中ADK缺乏的程度，从而有助于减少炎症反应和抑制动脉粥样硬化。在特定的目标1中，我们将研究内皮ADK缺乏对动脉内皮炎症粘附性降低的影响以及动脉粥样硬化病变的抑制形成。在特定的目标2到4中，我们将研究单核细胞ADK缺乏对单核细胞募集到动脉粥样硬化动脉的下降，巨噬细胞激活和泡沫细胞形成以及晚期动脉粥样硬化病变的生长的影响。我们还将确定PI3K/AKT和腺苷受体2a（A2AR）对ADK缺乏效果的贡献。这些研究将对使用ADK抑制剂作为预防和治疗动脉粥样硬化及其并发症的治疗剂具有重要意义。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis.

细胞内腺苷调节内皮细胞的表观遗传编程以促进血管生成

DOI：
10.15252/emmm.201607066
发表时间：
2017-09
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Xu Y;Wang Y;Yan S;Zhou Y;Yang Q;Pan Y;Zeng X;An X;Liu Z;Wang L;Xu J;Cao Y;Fulton DJ;Weintraub NL;Bagi Z;Hoda MN;Wang X;Li Q;Hong M;Jiang X;Boison D;Weber C;Wu C;Huo Y
通讯作者：
Huo Y

Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation.

通过腺苷激酶调节内皮细胞内腺苷表观遗传调节血管炎症

DOI：
10.1038/s41467-017-00986-7
发表时间：
2017-10-16
期刊：
Nature communications
影响因子：
16.6
作者：
Xu Y;Wang Y;Yan S;Yang Q;Zhou Y;Zeng X;Liu Z;An X;Toque HA;Dong Z;Jiang X;Fulton DJ;Weintraub NL;Li Q;Bagi Z;Hong M;Boison D;Wu C;Huo Y
通讯作者：
Huo Y

Metformin and metabolic diseases: a focus on hepatic aspects.