Macrophage Dysfunction in Obesity, Diabetes and Atherosclerosis

炎性巨噬细胞聚集是脂肪组织(AT)和其他代谢的共同特征 器官和动脉粥样硬化斑块中。糖尿病进一步加剧巨噬细胞含量和炎症， 在小鼠模型中，它会阻碍动脉粥样硬化的消退；在肥胖症中，它会导致胰岛素抵抗。这个 这一计划的首要假设是巨噬细胞存在潜在的因子和途径 动脉粥样硬化斑块和AT中的积聚和炎症是组织位置无关的， 代表常见的机制，以及组织部位依赖的，代表由 局部微环境。我们的计划将测试影响斑块或AT巨噬细胞含量的机制 糖尿病或饮食诱导的肥胖中的炎症状态与四个关键过程有关：招募 单核细胞、巨噬细胞滞留/停滞、巨噬细胞炎症/极化(M1与M2)和巨噬细胞 调节新陈代谢。为此，我们开发了如下三个项目：项目1将测试 这些概念在糖尿病动脉粥样硬化减少后受损消退的背景下 高脂血症；项目2和项目3将在高脂肪介导的饮食诱导的肥胖中测试这些概念 喂食。在这一高度协同的计划中，通过协调和系统的研究，每个项目将 确定糖尿病和糖尿病前期胰岛素抵抗中的联系、相互作用和调节层次 候选因素和新因素驱动巨噬细胞含量和炎症的状态。通过比较 结果通过斑块和AT，我们将识别那些共同和不同的通路 机械装置。所有这三个项目都将测试在小鼠巨噬细胞中的发现与经过管理的数据库的相关性 人单核/巨噬细胞和从瘦人和肥胖者身上提取的AT巨噬细胞。在……里面 “概念验证”研究，所有三个项目都将测试针对关键通路的新型治疗剂 在小鼠模型中以高度协同的方式进行研究。总而言之，我们的最终目标是确定 抑制巨噬细胞过度聚集和炎症的新治疗方法 增加临床心血管风险。

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.