Neutral sphingomyelinase-2 and glucocorticoid receptor

PRIME奖摘要 导致老年人死亡的一些主要原因是与以下方面有关的一些慢性病 持续性低度炎症，IL-1β在其中起中心作用。低品位的道路之一 炎症是通过干扰宿主的维持能力而导致衰老相关疾病的 动态平衡。前一个资助时期的实验为一种新的途径提供了证据，通过 其中炎症可能恶化一个主要的调节机制。具体来说，我们发现IL-1β增加 糖皮质激素受体的水平，这一影响在老年动物中尤其强烈，导致 对糖皮质激素的反应。本研究旨在探讨IL-1β调控血管紧张素转换酶的机制及影响。 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做到这一点， 一种对公共健康至关重要的健康状况，这种情况在老年人中很常见，在某些情况下 病例，可能进展为非酒精性脂肪性肝病。在目标1中，一系列体外研究将确定 IL-1β诱导GR水平升高的机制及其在脑内的作用 肝细胞。一种候选方法，与使用ChipSeq和 基因芯片将决定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 体内采用饮食诱导的小鼠脂肪变性和代谢综合征模型。IL-1β应答的大小 在体内或体外，通过靶向其信号级联的关键成分来调节肝细胞中的信号， NSMase2。对脂肪生成、糖异生和胰岛素敏感性的影响将是主要读数。 糖皮质激素过敏是许多衰老相关疾病的基础。糖皮质激素的长期使用 因为治疗炎症与显著的副作用有关，特别是在老年人中。因此， 通过揭示在衰老过程中调节肝脏糖皮质激素反应的机制，建议的 研究有可能既发现衰老的基本机制，也发现治疗衰老的新方法 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.