Sleep Loss and Inflammation in the Neurovascular Unit

 描述(由申请人提供)： 齐林斯基博士的研究重点是了解炎症如何调节睡眠的机制，以及睡眠不足和疾病是如何激活炎症的。目前，齐林斯基博士是博士后研究员 在波士顿医疗系统退伍军人事务部的拉迪卡·巴希尔博士的指导下。与普通人群相比，退伍军人睡眠障碍和睡眠障碍的患病率更高，包括那些导致睡眠缺失的睡眠障碍。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性物质。大脑中这些炎性分子的增强与嗜睡、认知障碍和包括失眠在内的睡眠障碍有关。然而，与失眠有关的这些炎症过程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，证明睡眠不足会激活富含亮氨酸的核苷酸蛋白-3炎症体蛋白复合体，该复合体是在细胞外三磷酸腺苷水平增加时形成的，以激活caspase-1并将白细胞介素1的前体裂解为其成熟的活性形式，并增强睡眠和脑电增量功率(0.5-4赫兹范围；睡眠需要的指标)。有趣的是，脑血流量与睡眠状态和脑电增量功率的变化有关，而白细胞介素1β是一种有效的血管扩张物质，促进脑血流量，提示了共同的机制联系。神经血管单位由不同类型的细胞组成，包括小胶质细胞、脑巨噬细胞、星形胶质细胞和神经元，这些细胞感知神经元的活动和功能来改变脑血流，以维持动态平衡，使其免受致病和正常生理活动的影响。神经血管单位通过释放包括白介素1β在内的炎性物质来做到这一点，白介素1β是一种促进大脑血液流动和睡眠的分子。这项研究的目标是确定由睡眠不足引起的能量相关机制如何激活炎症机制，即炎症小体，从而改变睡眠和脑血流。目的1验证睡眠减少增强能量底物以激活炎症小体从而提高睡眠的假说。目的2研究睡眠不足激活神经血管单位细胞内炎症体的假说。目的3检验睡眠不足增强白细胞介素1β以改变睡眠状态下脑血流量的假说。这项提案的发现将有助于了解睡眠不足引发的炎症机制，从而为经历衰弱睡眠障碍的退伍军人找到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、大脑免疫功能和脑血流研究方面的世界级领导者，这些研究将提供特殊的培训和指导，以确保成功完成这项提案。此外，退伍军人事务部职业发展奖将提供免疫学、细胞学和神经科学技术方面的重要培训，使Zielinski博士能够实现他的长期目标，即成为退伍军人事务部研究界的一名独立科学家，为帮助退伍军人的睡眠研究领域做出重大贡献。

 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.