Circadian Clock Disruption and Ischemic Stroke Outcomes: Age and Sex Differences
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abstract
Circadian clocks throughout the body provide for the local coordination of tissue- or cell-specific processesincluding the homeostatic regulation of key endocrine signals, growth factors and cytokines that mediatecardiovascular health. Circadian rhythm desynchronization, in the form of jet lag, shift work and irregular sleeppatterns, has been shown to increase the risk for stroke as well as exacerbate stroke severity/recovery. Atpresent, little is known about how circadian dysregulation interacts with other non-modifiable risk factors suchas biological sex and advancing age to modulate the pathophysiology of stroke. The proposed experiments willuse 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. Theprimary objectives of these studies are to determine whether the effects of circadian rhythm dysregulationduring early adulthood persist after intervening stable light-dark entrainment (for 3mo) so as to promote achronic basal pro-inflammatory state and thus exacerbate the pathophysiological severity of strokes that occurin 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 circadianrhythm desynchronization on the differential activation of pro-inflammatory cytokines, and on stroke-inducedbrain damage and functional deficits. Overall, the objectives of this project are to establish a translationalmodel that closely replicates epidemiologic data, and to promote the development of therapeutic interventionsor other strategies (e.g., adaptive changes in industry standards for managing shift work duration andschedules) for reducing stroke risk and severity in individuals with a history of shift work or irregular schedules.
