Role of Inflammation in Vascular Disease in the Metabolic Syndrome and Diabetes

代谢综合征和2型糖尿病已经成为相当大的公共卫生问题 由于问题的严重性和相关的动脉粥样硬化的高风险而产生的重要性 心血管疾病。新证据支持心血管疾病风险增加这一日益严重的问题 在1型糖尿病患者中，部分原因是血糖的直接影响和这一人群中不断演变的肥胖。 总体上统一的主题是代谢综合征和糖尿病的组成部分导致加速 动脉粥样硬化率由血管壁和血管内关键免疫和炎症信号的激活引起 脂肪细胞。这些因素进一步诱导关键细胞成分向脂肪中迁移和激活。 组织和血管壁。目标1--需要检验的假设是遗传或饮食诱导的胰岛素 耐药性和糖尿病将导致炎症加速、动脉粥样硬化和巨噬细胞浸润。 进入脂肪组织。我们将首先在新的小鼠和猪的模型中表征动脉粥样硬化的进展 糖尿病和代谢综合征。将研究的其他关键参数包括分析 内脏脂肪分布(使用DEXA)循环脂肪因子的产生和贩运的评估 巨噬细胞进入内脏脂肪床与项目4合作。目标2--这个目标的目标是 明确评估12/15脂氧合酶(12/15-LO)和炎症途径在内脏中的作用 与代谢综合征和糖尿病相关的血管疾病中的脂肪细胞和巨噬细胞。 该假说认为12/15-LO激活参与了血管壁下游炎症和 内脏脂肪组织在很大程度上通过诱导巨噬细胞的激活和运输而产生。目标3？这是 旨在检验这样一种假设，即包括Toll样受体在内的先天免疫系统的关键组件 4(TLR4)和IL-12家族细胞因子参与胰岛素抵抗和糖尿病患者的动脉粥样硬化 模特们。整个项目将利用所有核心，并涉及与Natarajan博士、McNamara博士、 莱伊、海德里克、格瑞蒂、苏珊娜·凯勒和诺伯特·莱廷格。我们项目的竞争性续签将 利用最新的细胞和分子方法和动物模型来探索机制和新的 减少或预防与以下相关的动脉粥样硬化性心血管疾病的翻译机会 糖尿病和代谢综合征。

The metabolic syndrome and type 2 diabetes have emerged as public health issues of considerable importance due to the magnitude of the problem and the associated high risk of atherosclerotic cardiovascular disease. New evidence supports a growing issue of increases in cardiovascular disease risk in people with Type 1 diabetes in part due to direct effects of glucose and evolving obesity in this population. The overall unifying theme is that components of the metabolic syndrome and diabetes leads to accelerated rates of atherosclerosis due to activation of key immune and inflammatory signals in the vascular wall and adipocytes. These factors further induce migration and activation of key cellular components into adipose tissue and the vascular wall. Aim#1--The hypothesis to be tested is that genetic or diet induced insulin resistance and diabetes will lead to accelerated inflammation, atherosclerosis, and macrophage infiltration into fat tissue. We will first characterize atherosclerosis progression in new mouse and porcine models of diabetes and the metabolic syndrome. The other key parameters that will be studied include analysis of visceral fat distribution (using DEXA) circulating adipokine production and evaluation of trafficking of macrophages into the visceral fat bed in collaboration with project 4. Aim#2--The goal of this aim is to specifically evaluate the role of 12/15 lipoxygenase (12/15-LO) and inflammatory pathways in visceral adipocytes and macrophages in vascular disease associated with the metabolic syndrome and diabetes. The hypothesis is that 12/15-LO activation participates in downstream inflammation in the vascular wall and visceral adipose tissue in large part by inducing activation and trafficking of macrophages. Aim#3?This is designed to test the hypothesis that key components of the innate immune system including toll like receptor 4 (TLR4) and the IL-12 family of cytokines participate in atherosclerosis in the insulin resistant and diabetic models. This overall project will utilize all cores and involve collaborations with Drs. Natarajan, McNamara, Ley, Hedrick, Gerrity, Susanna Keller, and Norbert Leitinger. The competitive renewal of our Project will utilize the latest cellular and molecular approaches and animal models to explore the mechanisms and new translational opportunities to reduce or prevent atherosclerotic cardiovascular disease associated with diabetes and the metabolic syndrome.