Neutral sphingomyelinase-2 and glucocorticoid receptor

Prime Award的简介 老年人死亡的一些主要原因是一些慢性病， 持续性低度炎症，其中IL-1β发挥核心作用。其中一条小路， 炎症导致衰老相关疾病的原因是干扰宿主维持免疫功能的能力。 体内平衡上一个资助期的实验为新途径提供了证据， 这种炎症可能恶化一种主要的调节机制。具体来说，我们发现IL-1β增加， 糖皮质激素受体的水平，一种在老年动物中特别有效的作用，导致增强的 对糖皮质激素的反应。该提案研究了IL-1β控制的机制和影响， 老年人的糖皮质激素依赖功能。拟议的研究将在脂肪肝的背景下进行， 这是一种对公共卫生至关重要的疾病，在老年人中很常见，在一些 例，可能进展为非酒精性脂肪肝。在目标1中，一系列体外研究将确定 IL-1β诱导GR水平升高的机制，并描述了IL-1β诱导GR水平升高的一些功能后果。 肝细胞通过使用ChipSeq的无偏全基因组分析验证的候选方法和 mRNA芯片将确定IL-1β对GR依赖的基因转录调控的影响程度 在肝脏中的表达。具体目标2致力于研究IL-1β对GR反应的影响， 使用脂肪变性和代谢综合征的饮食诱导的小鼠模型在体内进行。IL-1β反应的幅度 将通过靶向其信号级联的关键组分在体内或体外调节， nSM酶2。对脂肪生成、脂肪生成和胰岛素敏感性的影响将是主要的读数。 糖皮质激素超敏反应是许多衰老相关疾病的基础。糖皮质激素的长期应用 用于治疗炎症与显著的副作用相关，特别是在老年人中。因此，我们认为， 通过揭示衰老过程中调节肝脏糖皮质激素反应的机制， 研究有可能发现衰老的基本机制，以及新的方法， 管理长期使用糖皮质激素的不良副作用。

Abstract from Prime Award Some of the leading causes of death among the elderly are a number of chronic conditions associated with persistent low-grade inflammation in which IL-1β has a central role. One of the paths by which low-grade inflammation contributes to aging-associated diseases is by interfering with the ability of the host to maintain homeostasis. The experiments from the previous funding period provided evidence for a novel pathway by which inflammation may deteriorate a major regulatory mechanism. Specifically, we found that IL-1β increases the levels of glucocorticoid receptor, an effect especially potent in aged animals, leading to an augmented response to glucocorticoids. This proposal investigates the mechanisms and impact of IL-1β control of glucocorticoid -dependent functions in the elderly. The proposed studies will do that in the context of fatty liver, a condition of paramount health importance for public health, which is frequent in the elderly and, in some cases, may progress to non-alcoholic fatty liver disease. In aim 1, a series of in vitro studies will identify the mechanisms for IL-1β-induced increases in GR levels and delineate some of the functional consequences in hepatocytes. A candidate approach paralleled by an unbiased genome wide analyses using ChipSeq and mRNA arrays will determine the degree of IL-1β impact on GR-dependent transcriptional regulation of gene expression in the liver. Specific aim 2 is dedicated to investigating the impact IL-1β has on GR responses in vivo using a diet-induced mouse model of steatosis and metabolic syndrome. The magnitude of IL-1β response in hepatocytes will be modulated in vivo or in vitro by targeting a key component of its signaling cascade, nSMase2. The consequences on lipogenesis, gluconeogenesis and insulin sensitivity will be main readouts. Glucocorticoid hypersensitivity underlies many aging-associated disease. The chronic used of glucocorticoids for the treatment of inflammation is associated with significant side effects, particularly in the elderly. Therefore, by uncovering the mechanisms that regulate glucocorticoid response in the liver during aging, the proposed studies have the potential to discover both basic mechanisms of aging, as well as novel approaches to manage unwanted side effects of chronic use of glucocorticoids.