RAGE/mDia1, Macrophage Trafficking and Inflammation in Regression of Diabetic Atherosclerosis

RAGE/mDia1、巨噬细胞运输和糖尿病动脉粥样硬化消退中的炎症

基本信息

批准号：
9257767
负责人：
Ravichandran Ramasamy
金额：
$ 63.66万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257767
关键词：
Acceleration Address Age Animals Aorta Area Arterial Fatty Streak Atherosclerosis Behavior Binding Biological Assay Bone Marrow Candidate Disease Gene Cardiovascular Diseases Cells Clinical Research Collagen Complement Cytoplasmic Tail Data Development Diabetes Mellitus Diabetic mouse Dyslipidemias Engineering Environment Exhibits Fluorescence Fostering Genetic Transcription Glucose Heart Diseases Hyperglycemia ITGAM gene Impairment In Vitro Inflammation Inflammatory Insulin Resistance Lasers Lead Lesion Ligands Link Lipids Low Density Lipoprotein Receptor LoxP-flanked allele Mediating Metabolic stress Metabolism Microvascular Dysfunction Modeling Morbidity - disease rate Mus Oxidative Stress Pathogenesis Pathway interactions Patients Pattern Pharmacology Plasma Population Pre-Clinical Model Process Property Receptor Activation Recruitment Activity Regulation Relative Risks Resistance Resolution Risk Role Signal Transduction Testing Therapeutic Transplantation aortic arch diabetic diabetic patient disorder risk early onset efficacy testing glucose metabolism improved insight macrophage macrovascular disease migration monocyte mortality mouse model non-diabetic novel novel therapeutics preclinical study programs receptor expression receptor for advanced glycation endproducts reconstitution response small molecule small molecule inhibitor trafficking transcriptome transcriptome sequencing transcriptomics type I diabetic western diet

项目摘要

Summary Cardiovascular disease (CVD) represents the major cause of morbidity and mortality in patients with diabetes. Despite aggressive management of levels of lipids and glucose, both types 1 and 2 diabetic patients exhibit earlier onset and more extensive atherosclerotic lesions than non-diabetic subjects, and the response to lipid- lowering strategies is significantly less robust than the beneficial effects noted in non-diabetic subjects. Preclinical studies in diabetic animals have shown accelerated progression and impaired regression of atherosclerotic plaques, as well as increased retention of macrophages (MØs) in plaques. We will focus on diabetes-driven mechanisms linked to impaired atherosclerosis regression and the specific role of MØ perturbation. Our proposed studies are built on the discovery that transplantation of aortic arches from Ldlr-/- mice into diabetic mice deficient in RAGE or its cytoplasmic domain binding partner, DIAPH1, required for RAGE signaling, display significantly improved plaque regression, independent of changes in plasma glucose or lipid levels, compared to wild-type diabetic mice. Our earlier studies demonstrated that activation of RAGE is a critical component of the vessel wall response to hyperglycemia and that RAGE-driven mechanisms accounted for the observed acceleration and progression of atherosclerosis. In this application, using models of hyperglycemia and insulin resistance (IR), we will test the hypothesis that the consequences of hyperglycemia and RAGE/DIAPH1-dependent mechanisms in MØs modulate MØ trafficking (recruitment & retentions/stasis), MØ inflammatory polarization and MØ metabolism and oxidative stress, mechanisms which converge to suppress regression of established atherosclerotic plaques in diabetes. We will test novel pharmacological antagonists of RAGE/DIAPH1 in our murine model of diabetic atherosclerosis regression. These studies will provide novel insights into diabetes specific mechanisms that promote MØ accumulation and impair regression, and foster the development of novel therapeutic adjuncts for diabetic atherosclerosis.

概括心血管疾病（CVD）是糖尿病患者发病和死亡的主要原因。尽管积极控制血脂和葡萄糖水平，1 型和 2 型糖尿病患者仍表现出与非糖尿病受试者相比，动脉粥样硬化病变发病更早、更广泛，并且对脂质的反应与非糖尿病受试者中观察到的有益效果相比，降低策略的效果明显较差。对糖尿病动物的临床前研究表明，糖尿病进展加速且消退受损动脉粥样硬化斑块，以及斑块中巨噬细胞 (MØs) 的滞留增加。糖尿病驱动机制与动脉粥样硬化消退受损相关以及 MØ 的具体作用我们提出的研究是建立在 Ldlr-/- 主动脉弓移植的发现之上的。将小鼠转化为缺乏 RAGE 或其细胞质结构域结合伴侣 DIAPH1 的糖尿病小鼠，这是 RAGE 信号传导，显示斑块消退显着改善，与血浆葡萄糖的变化无关或脂质水平，与野生型糖尿病小鼠相比，我们早期的研究表明，RAGE 的激活是血管壁对高血糖反应的关键组成部分以及 RAGE 驱动机制在此应用中，使用模型解释了观察到的动脉粥样硬化的加速和进展。对于高血糖和胰岛素抵抗（IR），我们将检验以下假设： MØs 中的高血糖和 RAGE/DIAPH1 依赖性机制调节 MØ 运输（招募和滞留/停滞），MØ炎症极化和MØ代谢和氧化应激，机制我们将测试新的药物，以抑制糖尿病中已形成的动脉粥样硬化斑块的消退。在我们的糖尿病动脉粥样硬化消退小鼠模型中，RAGE/DIAPH1 的药理学拮抗剂。这些研究将为促进 MØ 积累的糖尿病特定机制提供新的见解并损害消退，并促进糖尿病动脉粥样硬化新型治疗辅助剂的开发。