Circadian Rhythms and Internal Desynchronization

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Abstract/Project Summary A master pacemaker in the suprachiasmatic nucleus of the hypothalamus coordinates circadian rhythms throughout the body. The phase and period of these oscillations is controlled by environmental signals, principally light. Disruption of circadian organization, such as occurs in shift work and jet lag, compromises health through mechanisms that are poorly understood. We recently discovered duper, a hamster mutation which speeds up the circadian clock and markedly accelerates re-entrainment of behavioral rhythms upon a shift of the light:dark cycle. The duper mutation is not a change in the coding region of casein kinase or any other known clock gene, and seems not to affect the transcriptional- translational feedback loops responsible for cell autonomous oscillations. We will identify the mutant allele by fast homozygosity mapping. We will use qRT-PCR to examine effects of the duper allele upon circadian phase shifts of expression of core clock and clock-controlled genes in heart, liver, kidney, and muscle. Given that transcription of genes critical to metabolic function is controlled by multiple clock proteins or clock-dependent transcription factors, we will use RNA-Seq to reveal the extent of transcriptome-wide phase disruption that occurs within organs during shifts. We will use immunocytochemistry to examine effects of duper on regional SCN function, and factor the contribution of pacemaker vs. peripheral oscillators to the latency of re-entrainment. Finally, we will test the hypothesis that internal desynchronization of circadian rhythms is responsible for aggravation of dilated cardiomyopathy by repeated phase shifts in a commonly used hamster model. Hamsters have proven valuable in studies of biological rhythms, and they offer a unique tool for understanding heart disease. Circadian control of the preovulatory LH surge is well understood in this species and provides a model for control of subordinate oscillators by the hypothalamic pacemaker. Our work will shed light on the mechanisms of circadian desynchrony and allow us to test its role in disease. Given the importance of circadian organization in behavior and physiology, this research will reveal mechanisms that underlie pathologies of heart and lung, as well as changes in liver and kidney that contribute to hypertension and fibrosis. The results will also shed light on causes of sleep deficiencies and metabolic disorders, and are likely to lead to development of new therapies to improve human and animal health.