Investigating the metabolic effects and de novo establishment of circadian timing differences between brain and liver

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Project Summary/Abstract Circadian disruptions are strongly associated with metabolic dysfunction, yet the mechanisms by which the circadian and metabolic systems influence one another are unclear. Elucidating the relationship between the two systems is especially important because of the prevalence of both metabolic and circadian disruptions and the safety and tractability of the circadian system as a therapeutic target. To address this need, the proposed work will determine whether changes to the relative timing of the circadian oscillators in the brain, which houses the central clock (the suprachiasmatic nucleus, or SCN) and controls feeding and metabolic rate, and liver, which controls both glucose and fat metabolism, underlie light- and diet-induced metabolic disorders. This work will test the hypothesis that relative timing of the brain and the liver is disrupted by aberrant light exposure and/or maladaptive feeding, and that this relative timing is established under typical conditions by tissue- specific period changes stemming from circadian transcriptional regulation differences. The proposed work will test these hypotheses using mouse models of clock disruption, obesogenic diets, and altered light timing to investigate the relative timing of the brain and liver and how that timing can be tuned. The resulting understanding of the origin and plasticity of the endogenous relative timing between the two tissues will provide a framework for prevention and intervention from metabolic disease with circadian etiology. The fellowship training plan developed around the research project described above will combine skills that I have developed during my Ph.D. studies with the expertise of the laboratory of my sponsor. Specifically, I will take advantage of my extensive experience with circadian biology, particularly with regards to the SCN and its influence over physiological rhythms, as well as my training in the production, maintenance, data acquisition, and analysis of organotypic tissue cultures expressing circadian clock gene reporters. I will apply these skills to the metabolic research questions described above by taking advantage of the expertise in the Lazar Lab in metabolic and liver health and functional genomic techniques. The synergistic combination of my past experience and the expertise of the Lazar Lab will thoroughly broaden and deepen my scientific and technical skillset, which will aid me in my preparation for becoming an independent investigator. The proposed experiments will be carried out at the world-class University of Pennsylvania, which will provide technical support in the form of collaboration, expertise, and core facilities as well as career development support in the form of training sessions, guidance, and networking opportunities.