Sympathetic regulation of inflammation from sleep fragmentation

睡眠碎片引起的炎症的交感神经调节

• 批准号: 10201814
• 负责人: Noah Todd Ashley
• 金额: $ 42.98万
• 依托单位: WESTERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201814
• 关键词: Acute; Adrenal Glands; Adrenal Medulla; Adrenalectomy; Adult; Anti-Inflammatory Agents; Antiinflammatory Effect; Binding; Biomedical Research; Blood; Blood Pressure; Brain; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Chemicals; Child; Chronic; Cytokine Gene; Data; Development; Disease; Endocrinology; Epidemiology; Event; Exposure to; Funding; Gene Expression; General Adaptation Syndrome; Glucocorticoid Receptor; Glucocorticoids; Health; Hormonal; Hypothalamic structure; Hypoxia; Immune response; Immunohistochemistry; Immunology; Incidence; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Lead; Link; Liver; Measurement; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Microglia; Modernization; Morbidity - disease rate; Mus; Neurobiology; Neurosciences; Neurosecretory Systems; Obesity; Obstructive Sleep Apnea; Organ; Outcome; Oxidopamine; Patients; Peripheral; Pharmacology; Phenotype; Physiological; Pituitary Gland; Play; Prevalence; Production; Protein Array; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Serum; Shift-Work Sleep Disorder; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Societies; Spleen; Sympathectomy; Sympathetic Nervous System; Testing; Time; Tissues; biological adaptation to stress; cytokine; fighting; hypothalamic-pituitary-adrenal axis; immunocytochemistry; inflammatory milieu; interest; neuroinflammation; novel therapeutic intervention; novel therapeutics; poor sleep; prevent; protein expression; response; shift work; sleep abnormalities; sleep behavior; sleep onset; sleep regulation; training opportunity; undergraduate student

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.

项目概要 原发性睡眠异常（失眠、轮班工作和阻塞性睡眠呼吸暂停）会促进炎症 环境，并与心血管和代谢疾病的发展相关。然而， 人们对这些关系背后的机制知之甚少。拟议的研究检查荷尔蒙 使用药理学研究睡眠碎片化 (SF) 炎症反应的机制 方法在小鼠身上进行。我们实验室之前 R15 资助的研究检查了交感神经的影响 睡眠不足引起的炎症反应导致系统（SNS）激活。在此续订申请中，角色 下丘脑-垂体-肾上腺 (HPA) 轴的激活在调节急性和慢性炎症中发挥作用 将调查慢性 SF。目标 1 将检查糖皮质激素是否介导 SF 诱导的发作 炎症和小胶质细胞的激活，小胶质细胞是神经炎症的重要贡献者。具体来说，小鼠 将进行肾上腺切除术、假肾上腺切除术或肾上腺切除术并用外源性挽救 糖皮质激素，然后进行急性和慢性 SF。促炎和抗炎基因和蛋白质 将分别使用 RT-PCR 和多重 Luminex 蛋白阵列评估表达。 免疫细胞化学将用于评估小胶质细胞的激活。这些发现将通过以下方式得到验证 药理抑制糖皮质激素的产生和与糖皮质激素受体的结合。而不是一个 经典的抗炎作用，据预测糖皮质激素将引发 SF 诱导的炎症。目标2 将检查糖皮质激素释放的时间过程以及对急性和慢性的促炎反应 SF。总而言之，拟议的研究将评估肾上腺皮质反应的重要性 调节睡眠不足期间的炎症，并为本科生提供独特的培训机会 对进行内分泌学、免疫学和神经科学方面的生物医学研究感兴趣。