IKKBETA LINKS MACROPHAGE INFLAMMATION TO OBESITY-INDUCED ATHEROSCLEROSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肥胖与几种疾病有关。炎症是肥胖和相关疾病之间的常见联系。影响肥胖人群的两种疾病是胰岛素抵抗形式的糖尿病和动脉粥样硬化形式的冠状动脉疾病。这两种肥胖引起的并发症都与血管壁(动脉粥样硬化)或脂肪组织(胰岛素抵抗)的炎症有关。 导致动脉粥样硬化发生和发展的许多炎症途径由转录因子核因子B(NF-B)调节，核因子-B是先天和获得性免疫反应的中央协调者(8，9)。核因子B在各种刺激下被迅速激活，包括细胞因子、感染剂和活性氧(10)。IkK是IkK复合体的主要催化亚基，在典型的或经典的激活途径(11，12)中，它是由炎性介质如肿瘤坏死因子和白介素1激活所必需的。在过去的十年中，IKK已被确定为炎症和癌症等几种慢性疾病发病机制之间的关键分子联系。然而，IKK在动脉粥样硬化中的作用还没有得到彻底的研究。 已经在动物模型和人类的动脉粥样硬化和血管炎症反应中检测到IKK的激活(13-15)。尽管有强有力的证据表明IKK？激活参与了动脉粥样硬化的进展，但IKK？介导的巨噬细胞炎症功能在动脉粥样硬化中的作用仍不清楚。先前使用不同小鼠模型的研究给出了不一致的结果，迫切需要进一步的研究来确定巨噬细胞IKK在动脉粥样硬化中的作用。 初步数据表明，巨噬细胞中IKKβ的缺乏会促进炎症。此外，初步研究表明，巨噬细胞中IKKβ的缺乏可以减少饮食诱导的动脉粥样硬化。我们假设IKKbeta在巨噬细胞炎症与肥胖诱导的动脉粥样硬化和胰岛素抵抗之间起着重要的作用。研究将探讨巨噬细胞IKKbeta在饮食诱导的动脉粥样硬化和胰岛素抵抗实验模型中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity is associated with several diseases. Inflammation is a common link between obesity and associated diseases. Two such diseases influencing the obese population are diabetes in the form of insulin resistance, and coronary artery disease in the form of atherosclerosis. Both of these obesity-induced complications are associated with inflammation in either the blood vessel wall (atherosclerosis) or in adipose tissue (insulin resistance). Many inflammatory pathways that contribute to atherosclerosis initiation and development are regulated by transcriptional factor nuclear factor-¿B (NF-¿B), a central coordinator of the innate and adaptive immune responses (8, 9). NF-¿B is rapidly activated in response to various stimuli, including cytokines, infectious agents and reactive oxygen species (10). I¿B kinase ¿ (IKK¿) is the predominant catalytic subunit of the IKK complex that is required for activation of NF-¿B by inflammatory mediators such as TNF¿ and IL-1s in the canonical or classical activation pathway (11, 12). In the past decade, IKK¿ has been established as a critical molecular link between inflammation and pathogenesis of several chronic diseases such as cancer. However, the role of IKK¿ in atherosclerosis has not been thoroughly investigated. IKK¿ activation has been detected in atherosclerosis and in vascular inflammatory reactions in animal models and humans (13-15). Despite the strong evidence suggesting the involvement of IKK¿ activation in atherosclerosis progression, the role of IKK¿-mediated inflammatory functions by macrophages in atherosclerosis remain unclear. The previous studies using various mouse models have given inconsistent results and further research is urgently needed to define the role of macrophage IKK¿ in atherosclerosis. Preliminary data demonstrate that deficiency of IKKbeta in macrophages promotes inflammation. In addition, pilot studies indicate that deficiency of IKKbeta in macrophages reduces diet-induced atherosclerosis. We hypothesize that IKKbeta plays an important role linking macrophage inflammation to obesity-induced atherosclerosis and insulin resistance. Studies will address the role of macrophage IKKbeta in experimental models of diet-induced atherosclerosis and insulin resistance.