Macrophage Dysfunction in Obesity, Diabetes and Atherosclerosis

肥胖、糖尿病和动脉粥样硬化中的巨噬细胞功能障碍

• 批准号: 9209582
• 负责人: Edward A Fisher
• 金额: $ 242.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9209582
• 关键词: ASCL1 gene; Adipocytes; Adipose tissue; Affect; Animal Model; Arterial Fatty Streak; Atherosclerosis; Attenuated; Biochemistry; Bioinformatics; Biometry; Breeding; Cells; Chronic; Clinical; Data; Databases; Diabetes Mellitus; Diet; Dissection; Environment; Fatty acid glycerol esters; Functional disorder; Goals; Hematopoietic stem cells; Human; Hyperglycemia; Hyperlipidemia; Impairment; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Lead; Link; Lipids; Mediating; Metabolic; Metabolism; Microsurgery; Molecular; Morbidity - disease rate; Mus; Myelopoiesis; Obesity; Organ; Pathology; Pathway interactions; Prediabetes syndrome; Process; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Site; Testing; Thinness; Tissues; base; cardiovascular disorder risk; cardiovascular risk factor; diabetic; feeding; human subject; insight; macrophage; monocyte; mortality; mouse model; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; programs; small molecule inhibitor; targeted treatment; transcriptome sequencing; translational study; treatment strategy

Accumulation of inflammatory macrophages is a common feature in adipose tissue (AT) and other metabolic organs and in the atherosclerotic plaque. Diabetes further exacerbates macrophage content and inflammation, which in mouse models impairs atherosclerosis regression; and in obesity, drives insulin resistance. The overarching hypothesis of this Program is that there are factors and pathways underlying macrophage accumulation and inflammation in atherosclerotic plaques and AT that are tissue site-independent, representing common mechanisms, as well as tissue site-dependent, representing discrete regulation by the local micro-environments. Our Program will test the mechanisms affecting plaque or AT macrophage content and inflammatory states in diabetes or diet-induced obesity in relation to four key processes: recruitment of monocytes, macrophage retention/stasis, macrophage inflammation/polarization (M1 vs. M2), and macrophage regulation of metabolism. To accomplish this, we have developed three Projects as follows: Project 1 will test these concepts in diabetic atherosclerosis in the context of impaired regression after reduction of hyperlipidemia; and Projects 2 and 3 will test these concepts in diet-induced obesity mediated by high fat feeding. In this highly synergistic Program, through coordinated and systematic studies, each Project will identify the connections, cross talk, and regulatory hierarchies in the diabetic and pre-diabetic insulin resistant states by which candidate and novel factors drive macrophage content and inflammation. By comparing the results across the plaque and AT, we will identify those pathways that underlie both common and distinct mechanisms. All three Projects will test the relevance of findings in mouse macrophages to curated databases of human monocytes/macrophages and of AT macrophages retrieved from lean and obese human subjects. In “proof-of-concept” studies, all three Projects will test novel therapeutic agents targeting the key pathways under study in mouse models in a highly synergistic manner. Taken together, our ultimate goal is to identify novel therapeutic approaches to suppress exaggerated macrophage accumulation and inflammation that contribute to increased clinical cardiovascular risk.

炎症性巨噬细胞的积累是脂肪组织（AT）和其他代谢的共同特征 器官和动脉粥样硬化斑块。糖尿病进一步加剧了巨噬细胞含量和炎症， 在小鼠模型中会损害动脉粥样硬化的消退；在肥胖中，驱动胰岛素抵抗。这 该程序的总体假设是巨噬细胞的因素和途径 动脉粥样硬化斑块中的积累和炎症，在组织部位独立于 代表共同的机制以及组织位点依赖性，代表由 当地的微环境。我们的计划将测试影响斑块或巨噬细胞含量的机制 与四个关键过程有关的糖尿病或饮食引起的肥胖症的炎症状态：募集 单核细胞，巨噬细胞保留/停滞，巨噬细胞注射/极化（M1与M2）和巨噬细胞 新陈代谢的调节。为此，我们已经开发了三个项目：项目1将测试 在减少后，糖尿病动脉粥样硬化的这些概念 高脂血症；项目2和3将在高脂介导的饮食引起的肥胖症中测试这些概念 进食。在这个高度协同的计划中，通过协调和系统的研究，每个项目都将 确定糖尿病和糖尿病前胰岛素耐药性的连接，谈话和调节性层次结构 候选和新因素驱动巨噬细胞含量和炎症的状态。通过比较 在整个牌匾上的结果，我们将确定那些基于常见和独特的途径 机制。这三个项目将测试鼠标巨噬细胞中发现与策划数据库的相关性 人类的单核细胞/巨噬细胞以及从瘦肉和肥胖的受试者中检索的巨噬细胞。在 “概念验证”研究，这三个项目将测试针对关键途径的新型热剂 在小鼠模型中以高度协同的方式进行研究。综上所述，我们的最终目标是确定 抑制夸张的巨噬细胞积累和炎症的新型治疗方法 有助于增加临床心血管风险。