Sleep Loss and Inflammation in the Neurovascular Unit

 描述（由申请人提供）： 博士Zielinski的研究重点是了解炎症如何调节睡眠的机制，以及如何被睡眠不足和疾病激活。目前，Zielinski博士是一名博士后研究员， 在波士顿退伍军人事务部医疗保健系统的Radhika Basheer博士的指导下。与普通人群相比，退伍军人的睡眠障碍和睡眠障碍的患病率增加，包括那些导致睡眠丧失的疾病。睡眠不足会导致生产力下降、嗜睡、疲劳，并增加健康和记忆问题。睡眠不足会增加大脑中的炎症物质。大脑中这些炎症分子的增强与嗜睡、认知受损和睡眠障碍（包括失眠）有关。然而，控制这些炎症过程与睡眠不足相关的确切机制仍然知之甚少。我目前的研究提供了强有力的初步证据，证明富含核苷酸亮氨酸的蛋白质-3炎性体蛋白复合物，其形成是对细胞外三磷酸腺苷水平增加的反应，以激活半胱天冬酶-1并将白细胞介素-1 β的前体形式切割成其成熟的活性形式，被睡眠丧失激活，并增强睡眠和脑电图δ功率。（0.5- 4 Hz范围;睡眠需求的指标）。有趣的是，脑血流量与睡眠状态和脑电图δ功率的变化相关，白细胞介素-1 β是一种有效的血管舒张物质，可增强脑血流量，这表明了一种常见的机制联系。神经血管单位由不同的细胞类型组成，包括小胶质细胞、脑巨噬细胞、星形胶质细胞和神经元，其感测神经元活动并起作用以改变脑血流以维持来自致病性和正常生理活动的稳态。神经血管单位部分通过释放炎症物质来实现这一点，包括白细胞介素-1 β-一种增强脑血流和睡眠的分子。该提案的目标是确定睡眠不足引起的能量相关机制如何激活炎症机制，即炎性小体，以改变睡眠和脑血流量。目的1：验证睡眠缺失增强能量底物激活炎性小体以增强睡眠的假设。目的2：探讨睡眠不足激活神经血管单位细胞内炎性小体的假说。目的3检验睡眠不足增强白细胞介素-1 β改变睡眠状态下脑血流量的假设。这项提案的发现将有助于了解睡眠不足引起的炎症机制，以便为经历过睡眠障碍的退伍军人确定新的药物和治疗方法，包括失眠，创伤后应激障碍，创伤性脑损伤和精神分裂症。在退伍军人事务部波士顿医疗保健系统为这项提案聚集的导师和合作者团队是睡眠，脑免疫功能和脑血流研究的世界级领导者，他们将提供出色的培训和指导，以确保成功完成这项提案。此外，该退伍军人事务职业发展奖将提供免疫学，细胞和神经科学技术的重要培训，使Zielinski博士能够实现他的长期目标，成为退伍军人事务研究界的独立科学家，为睡眠研究领域做出重大贡献，帮助退伍军人。

 DESCRIPTION (provided by applicant): Dr. Zielinski's research is focused on understanding mechanisms of how inflammation regulates sleep and is activated by sleep loss and disease. Currently, Dr. Zielinski is a postdoctoral fellow under the mentorship of Dr. Radhika Basheer at the Veteran Affairs Boston Healthcare System. Compared to the general population, veterans have an increased prevalence of sleep disorders and sleep disturbances including those that induce sleep loss. Sleep loss causes lost productivity, sleepiness, fatigue, and increased health and memory problems. Sleep loss increases inflammatory substances in the brain. Enhancements in these inflammatory molecules in the brain are associated with sleepiness, impaired cognition, and sleep disorders including insomnia. However, the exact mechanisms governing these inflammatory processes in relation to sleep loss remain poorly understood. My current research has provided strong preliminary evidence that the nucleotide leucine-rich protein-3 inflammasome protein complex, which forms in response to increased extracellular adenosine tri-phosphate levels to activate caspase-1 and cleave the pro-form of interleukin-1 beta into its mature active form is activated by sleep loss and enhances sleep and electroencephalogram delta power (0.5- 4 Hz range; an indicator of sleep need). Interestingly, cerebral blood flow is associated with changes in sleep state and electroencephalogram delta power and interleukin-1 beta is a potent vasodilative substance enhancing cerebral blood flow suggesting a common mechanistic link. The neurovascular unit is comprised of different cell types including microglia, brain macrophages, astrocytes, and neurons that sense neuronal activity and function to alter cerebral blood flow to maintain homeostasis from pathogenic and normal physiologic activities. The neurovascular unit does this, in part, through releasing inflammatory substances including interleukin-1 beta-a molecule that enhances cerebral blood flow and sleep. The goal of this proposal is to determine how energy-related mechanisms induced by sleep loss activate a mechanism of inflammation, the inflammasome, to alter sleep and cerebral blood flow. Aim 1 tests the hypothesis that sleep loss enhances energy substrates to activate the inflammasome to enhance sleep. Aim 2 investigates the hypothesis that sleep loss activates the inflammasome in cells of the neurovascular unit. Aim 3 examines the hypothesis that sleep loss enhances interleukin-1 beta to alter cerebral blood flow during sleep states. Findings from this proposal will allow for an understanding of inflammatory mechanism induced by sleep loss so that novel pharmaceutical and treatments can be identified for veterans who experience debilitating disturbed sleep including those with insomnia, post-traumatic stress disorder, traumatic brain injury and schizophrenia. The team of mentors and collaborators assembled for this proposal at the Veteran Affairs Boston Healthcare System are world class leaders in sleep, brain immune function, and cerebral blood flow research that will provide exceptional training and guidance to ensure successful completion of this proposal. Further, this Veteran Affairs Career Development Award will provide important training in immunological, cellular, and neuroscience techniques that will enable Dr. Zielinski to achieve his long-term goal of becoming an independent scientist within the Veteran Affairs research community making significant contributions to the field of sleep research aiding veterans.