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

炎症在代谢综合征和糖尿病中血管疾病中的作用

• 批准号: 8098764
• 负责人: JERRY L. NADLER
• 金额: $ 24.95万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098764
• 关键词: Adipocytes; Adipose tissue; Animal Model; Arachidonate 15-Lipoxygenase; Atherosclerosis; Beds; Blood Vessels; Collaborations; DEXA; Diabetes Mellitus; Diet; Evaluation; Family; Family suidae; Fatty acid glycerol esters; Genetic; Glucose; Goals; Immune; Immune system; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Interleukin-12; Lead; Metabolic syndrome; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Population; Production; Public Health; Role; Signal Transduction; Testing; Tissues; Vascular Diseases; Visceral; cardiovascular disorder risk; cytokine; design; diabetic; high risk; macrophage; migration; prevent; toll-like receptor 4; trafficking

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.

代谢综合征和 2 型糖尿病已成为相当重要的公共卫生问题 由于问题的严重性和相关的动脉粥样硬化的高风险，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，部分原因是葡萄糖的直接影响和该人群不断发展的肥胖。 总体统一的主题是代谢综合征和糖尿病的组成部分导致加速 由于血管壁中关键免疫和炎症信号的激活而导致动脉粥样硬化的发生率 脂肪细胞。这些因素进一步诱导关键细胞成分迁移和激活到脂肪中 组织和血管壁。目标#1——要测试的假设是遗传或饮食诱导胰岛素 抵抗力和糖尿病会导致炎症、动脉粥样硬化和巨噬细胞浸润加速 进入脂肪组织。我们将首先表征新的小鼠和猪模型中的动脉粥样硬化进展 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运输评估 与项目 4 合作将巨噬细胞引入内脏脂肪床。目标#2——该目标的目标是 专门评估 12/15 脂氧合酶 (12/15-LO) 和炎症通路在内脏中的作用 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。 假设 12/15-LO 激活参与血管壁的下游炎症，并且 内脏脂肪组织在很大程度上是通过诱导巨噬细胞的激活和运输来实现的。目标#3？这是 旨在检验先天免疫系统的关键组成部分（包括 Toll 样受体）的假设 4 (TLR4) 和 IL-12 细胞因子家族参与胰岛素抵抗和糖尿病患者的动脉粥样硬化 模型。这个整体项目将利用所有核心并涉及与博士的合作。纳塔拉扬、麦克纳马拉、 莱伊、赫德里克、格里蒂、苏珊娜·凯勒和诺伯特·雷廷格。我们项目的竞争性更新将 利用最新的细胞和分子方法以及动物模型来探索机制和新的 减少或预防与以下疾病相关的动脉粥样硬化性心血管疾病的转化机会 糖尿病和代谢综合征。