Oxidative Stress Responses to Loss and Recovery of Sleep

描述(由申请人提供)：被广泛接受的两个概念是：睡眠剥夺损害健康和睡眠恢复具有动态康复能力。提出这项研究的理由是，目前还没有确定特定的组织在睡眠剥夺后需要修复或通过睡眠恢复来“恢复”。我们的长期目标是提供生理过程和结果的有形证据，这些过程和结果构成了睡眠和睡眠缺失的属性。在动物模型中，睡眠剥夺会产生一种最终变得高度致命的情况，缺乏特定的定位，并且与睡眠是可逆的，这意味着通过生化过程或功能异常来调节。最近在睡眠剥夺大鼠身上的发现提供了证据，表明缺失的生物中介是氧化应激和抗氧化剂枯竭。这项建议的目的是确定氧化应激相关损伤的靶点，并确定抗氧化剂耗竭和细胞损伤影响生理和临床体征的程度。中心假说是，在多种调节系统中，抗氧化剂状态的降低会导致可修复和不可修复的细胞损伤广泛增加，最终导致补偿不足和病理生理迹象的发展。初步数据支持这一假说的形成，因为它提供了因睡眠不足而导致氧化应激引起的肝组织DNA损伤和细胞凋亡增加的证据。在再次允许睡眠之前，抗氧化酶不能起到补偿作用。在目标1下的实验中，将确定大鼠在睡眠缺失和恢复期间氧化应激对细胞脂质、蛋白质和DNA靶标的损害以及特定器官系统的损害定位。目标2下的实验将确定在睡眠丧失和恢复期间导致细胞死亡和增加细胞修复和更新的细胞损伤程度。目标3下的研究将测试抗氧化剂状态的操纵可以在多大程度上改变睡眠剥夺导致的细胞损伤和生理迹象。这项拟议的研究是合作的，整合了睡眠生理学和自由基生物学方面的专业知识。研究设计由不同睡眠剥夺时间、睡眠限制和控制条件的计划比较组成。分析方法包括生化、免疫分析和免疫组织化学方法。这项拟议的研究的意义在于促进睡眠恢复功能的医学干预措施的进步。

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.