Sympathetic regulation of inflammation from sleep fragmentation

项目摘要 原发性睡眠异常（失眠、轮班工作和阻塞性睡眠呼吸暂停）促进炎症性 环境中，并与心血管和代谢疾病的发展。但 对这些关系的基本机制知之甚少。这项拟议中的研究检查了荷尔蒙 使用药理学方法研究睡眠片段化（SF）炎症反应的基础机制 接近老鼠。我们实验室以前的R15资助的研究检查了交感神经的影响， 系统（SNS）激活对睡眠丧失的炎症反应。在此更新应用程序中， 下丘脑-垂体-肾上腺（HPA）轴的激活在调节急性和慢性炎症中起作用。 将研究慢性SF。目的1将检测糖皮质激素是否介导SF诱导的 炎症和小胶质细胞的激活，神经炎症的重要贡献者。具体来说，老鼠 肾上腺切除术、假肾上腺切除术或肾上腺切除术后用外源性 糖皮质激素，然后进行急性和慢性SF。Pro和Pro基因和蛋白质 分别使用RT-PCR和多重Luminex蛋白阵列评估表达。 将使用免疫细胞化学评估小胶质细胞活化。这些发现将通过以下方式得到验证： 药理学抑制糖皮质激素产生和与糖皮质激素受体结合。而不是 经典的抗炎作用，预测糖皮质激素将引发SF诱导的炎症。目的2 将检查糖皮质激素释放的时间过程和急性和慢性炎症反应， SF.综上所述，拟议的研究将评估肾上腺皮质反应的重要性， 在睡眠丧失期间调解炎症，并为本科生提供独特的培训机会 对内分泌学、免疫学和神经科学的生物医学研究感兴趣。

Project Summary Primary sleep abnormalities (insomnia, shift work, and obstructive sleep apnea) promote an inflammatory environment and are associated with the development of cardiovascular and metabolic disease. However, the mechanisms underlying these relationships are poorly understood. The proposed research examines hormonal mechanisms that underlie the inflammatory response to sleep fragmentation (SF) using pharmacological approaches in mice. Previous R15-funded research in our lab examined the effect of sympathetic nervous system (SNS) activation upon inflammatory responses to sleep loss. In this renewal application, the role that activation of the hypothalamic-pituitary-adrenal (HPA) axis plays in modulating inflammation from acute and chronic SF will be investigated. Aim 1 will examine whether glucocorticoids mediate the onset of SF-induced inflammation and the activation of microglia, an important contributor to neuroinflammation. Specifically, mice will be adrenalectomized, sham-adrenalectomized, or adrenalectomized and rescued with exogenous glucocorticoids and then subjected to acute and chronic SF. Pro- and antiinflammatory gene and protein expression will be assessed using RT-PCR and multiplex Luminex protein arrays, respectively. Immunocytochemistry will be used to assess microglia activation. These findings will be validated through pharmacological inhibition of glucocorticoid production and binding to glucocorticoid receptors. Instead of a classic anti-inflammatory effect, it is predicted that glucocorticoids will prime SF-induced inflammation. Aim 2 will examine the time course of glucocorticoid release and pro-inflammatory responses to acute and chronic SF. Taken together, the proposed research will assess the importance of the adrenocortical response in mediating inflammation during sleep loss, and provide unique training opportunities for undergraduates interested in conducting biomedical research in endocrinology, immunology, and the neurosciences.