Oxidative Stress Responses to Loss and Recovery of Sleep

描述（由申请人提供）：广泛接受的是两个概念：睡眠剥夺损害健康和睡眠恢复具有动态愈合能力。提出这项研究的理由是，尚未确定特定组织在睡眠剥夺后需要修复或通过睡眠恢复“恢复”。我们的长期目标是提供构成睡眠和睡眠丧失特性的生理过程和结果的切实证据。在动物模型中，睡眠剥夺会产生一种最终变得高度致命的病症，缺乏特定的定位，并且随着睡眠而可逆，这意味着通过生化过程或功能异常进行调解。最近在睡眠剥夺大鼠中的发现提供了证据，证明缺失的生物介导是氧化应激和抗氧化剂消耗。本提案的目的是确定氧化应激相关损伤的靶点，并确定抗氧化剂消耗和细胞损伤影响生理和临床体征的程度。核心假设是，抗氧化状态的减少会导致多个调节系统内可修复和不可修复的细胞损伤的广泛增加，最终导致补偿不足和病理生理学体征的发展。初步数据支持这一假设的制定提供证据的增加DNA损伤和细胞凋亡的肝组织经历氧化应激引起的睡眠不足。抗氧化酶无法做出补偿反应，直到再次允许睡眠。在目标1下的实验中，将在大鼠睡眠丧失和恢复期间确定氧化应激对细胞脂质、蛋白质和DNA靶点的损伤以及对特定器官系统的损伤的定位。目标2下的实验将确定导致细胞死亡的细胞损伤程度，以及在睡眠丧失和恢复期间增加细胞修复和更新的程度。目标3下的研究将测试抗氧化状态的操作可以在多大程度上改变睡眠剥夺引起的细胞损伤和生理体征。拟议的研究是合作的，并整合了睡眠生理学和自由基生物学的专业知识。研究设计包括有计划地比较不同持续时间的睡眠剥夺、睡眠限制和控制条件。分析包括生物化学、免疫测定和免疫组织化学方法。这项研究的意义在于促进睡眠恢复功能的医疗干预措施的进步。

DESCRIPTION (provided by applicant): Widely accepted are two notions: sleep deprivation impairs health and sleep recovery has dynamic healing powers. The rationale for the proposed research is that specific tissues have not yet been identified as being in need of repair after sleep deprivation or "restored" by sleep recovery. Our long-term goal is to provide tangible evidence of physiological processes and outcomes that compose the properties of sleep and sleep loss. Sleep deprivation in the animal model produces a condition that eventually becomes highly lethal, lacks specific localization, and is reversible with sleep, implying mediation by a biochemical process or functional abnormality. Recent findings in sleep-deprived rats have provided evidence that the missing biological mediation is oxidative stress and antioxidant depletion. The objectives of this proposal are to identify targets of oxidative stress-associated damage and to determine the extent to which antioxidant depletion and cell damage affect physiological and clinical signs. The central hypothesis is that reductions in antioxidant status cause widespread increases in repairable and irreparable cell damage within multiple regulatory systems, leading ultimately to inadequate compensation and to the development of pathophysiological signs. Preliminary data support the formulation of this hypothesis by providing evidence of increased DNA damage and apoptosis in hepatic tissue undergoing oxidative stress induced by sleep loss. Antioxidant enzymes fail to respond in compensation until sleep is again permitted. In experiments under Aim 1, damage to cellular lipid, protein, and DNA targets of oxidative stress and localization of damage to specific organ-systems will be determined in rats during sleep loss and recovery. Experiments under Aim 2 will determine the extent of cell injury leading to cell death and to increased cell repair and renewal during sleep loss and recovery. Studies under Aim 3 will test the extent to which manipulation of antioxidant status can change sleep deprivation-induced cell damage and physiological signs. The proposed research is collaborative and integrates expertise in sleep physiology and free radical biology. The research design is composed of planned comparisons of different durations of sleep deprivation, sleep restriction, and control conditions. Analyses include biochemical, immunoassay, and immunohistochemical methods. The significance of the proposed research is advancement of medical interventions that promote the restorative functions of sleep.