Integrated stress response and the circadian clock

Project Summary The overall objective of this proposal is to elucidate specific crosstalk mechanisms between the integrated stress response (ISR) and circadian timekeeping, two fundamental biological processes in neurons. Circadian rhythm regulates neuronal differentiation, plasticity, and tissue regeneration and its disruption contributes to a variety of human health problems. Circadian clock genes are widely expressed in almost all cells. To function properly, the cellular clock must integrate and synchronize with cellular physiology and metabolism. ISR is a conserved intracellular signaling network for cells to respond to stressors and restore homeostasis. Little is known, however, on whether and how ISR integrates with the circadian clock, which forms a major gap in our understanding of homeostatic integration in neurons. Our recently published work indicates that ISR may be a conserved mechanism that couples cellular stress response to circadian timekeeping. Based on the published work and unpublished preliminary data, here we propose to test the overall hypothesis that ISR interacts with the mammalian circadian clock: ISR regulates fundamental clock properties including entrainment and circadian period, whereas the clock controls ISR response based on the time of day. We will leverage our expertise and unique mouse models to test the hypothesis using a combination of molecular, cellular, and behavioral approaches. Aim 1 will define a role for the ISR inhibitor IMPACT (imprinted and ancient gene protein) in regulating photic entrainment of the circadian clock. Aim 2 will identify a role for unfolded protein response and PERK (protein kinase R-like endoplasmic reticulum kinase) in circadian timekeeping. Aim 3 will elucidate eIF2 (eukaryotic translation initiation factor 2)-dependent translational control mechanisms in the circadian clock. The proposed work is innovative, because it utilizes new mouse genetic tools to address conceptually novel questions regarding the crosstalk mechanisms between ISR and the clock. The contributions are expected to be significant, because it is expected to uncover mechanistic links between the two fundamentally important cellular processes. Importantly, ISR frequently goes awry in complex brain disorders, which are often associated with disrupted daily rhythms in patients due to unknown mechanisms. As ISR can be targeted by FDA-approved drugs, understanding its role in circadian physiology may offer new opportunities to regulate the body clock function and to treat clock dysfunctions in these diseases.