Circadian Clock Disruption and Ischemic Stroke Outcomes: Age and Sex Differences

整个身体的生物钟提供组织或细胞特异性过程的局部协调 包括关键内分泌信号、生长因子和细胞因子的稳态调节， 心血管健康昼夜节律失调，表现为时差反应、轮班工作和睡眠不规律 模式，已被证明会增加中风的风险，以及加剧中风的严重程度/恢复。在 目前，关于昼夜节律失调如何与其他不可改变的风险因素相互作用， 生理性别和年龄的增长来调节中风的病理生理学。拟议的实验将 使用已建立的大鼠模型来研究昼夜节律失调与两种非 可改变的危险因素，生物性别和年龄，调节缺血性卒中的致病反应。的 这些研究的主要目的是确定昼夜节律失调的影响是否 在成年早期，干预稳定的明暗诱导（持续3个月）后持续存在，以促进 慢性基础促炎状态，并因此加剧发生的中风的病理生理严重性 在中年（10个月），当中风的易感性增加，在两个性别。成人比较（5个月） 雄性和雌性大鼠将被用来确定性别差异的“后”或素质的影响，昼夜节律 节律去极化对促炎细胞因子的差异活化和对中风诱导的 脑损伤和功能缺陷。总的来说，本项目的目标是建立一个翻译 密切复制流行病学数据的模型，并促进治疗干预措施的发展 或其它策略（例如，管理轮班工作时间的行业标准的适应性变化， 时间表），用于降低有轮班工作史或不规则时间表的个体的中风风险和严重程度。

Circadian clocks throughout the body provide for the local coordination of tissue- or cell-specific processes including the homeostatic regulation of key endocrine signals, growth factors and cytokines that mediate cardiovascular health. Circadian rhythm desynchronization, in the form of jet lag, shift work and irregular sleep patterns, has been shown to increase the risk for stroke as well as exacerbate stroke severity/recovery. At present, little is known about how circadian dysregulation interacts with other non-modifiable risk factors such as biological sex and advancing age to modulate the pathophysiology of stroke. The proposed experiments will use an established rat model to study how interactions between circadian rhythm dysregulation and two non- modifiable risk factors, biological sex and aging, modulate pathogenic responses to ischemic stroke. The primary objectives of these studies are to determine whether the effects of circadian rhythm dysregulation during early adulthood persist after intervening stable light-dark entrainment (for 3mo) so as to promote a chronic basal pro-inflammatory state and thus exacerbate the pathophysiological severity of strokes that occur in middle age (10mo of age), when stroke susceptibility increases in both sexes. Comparisons of adult (5mo) male and female rats will be used to identify sex differences in the “after” or diathetic effects of circadian rhythm desynchronization on the differential activation of pro-inflammatory cytokines, and on stroke-induced brain damage and functional deficits. Overall, the objectives of this project are to establish a translational model that closely replicates epidemiologic data, and to promote the development of therapeutic interventions or other strategies (e.g., adaptive changes in industry standards for managing shift work duration and schedules) for reducing stroke risk and severity in individuals with a history of shift work or irregular schedules.