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.
Stroke is the fourth major cause of death and the leading non-martial cause of long-term disability in the United States. Because alterations of 24-hour or circadian rhythms imposed by our everyday irregular work and/or social environments have been linked to vascular disease, the proposed research will examine sex differences in the extent to which shift-work schedules exacerbate brain injury and functional deficits caused by ischemic stroke. With new information on how circadian rhythm dysregulation induces chronic/persistent pro- inflammatory conditions that amplify stroke pathology, this project is expected to establish a translational model that closely replicates epidemiologic data and to stimulate the development of therapeutic interventions for reducing stroke risk and severity in individuals with a history of shift work or irregular schedules.
