Metabolic dysfunction is a major risk factor to foster aging and chronic diseases. Vast amount of evidences have linked metabolic disorders to cardiovascular disease, type 2 diabetes mellitus, cancer, and now likely to neurological disorders including psychiatric illnesses and neurodegeneration. We are interested in finding solutions to correct metabolic disorders from two different angles, i.e., via pathways to strengthen the circadian control, and genetic longevity models to interrupt the imbalances.
Circadian clock is an intrinsic, time-tracking system that assists most living organisms in responding to the daily, 24-hour environmental change. In mammals, the central circadian oscillation is achieved by light entrainment to the suprachiasmatic nucleus (SCN), which in turn synchronizes peripheral clocks. The coordinated central and peripheral clocks ensure the correct relays of external cues to behavior and metabolic outputs such as sleep, feeding, and oxidative metabolism and gluconeogenesis. Notably, longevity factors, e.g., Sirtuins and AMPK are also recognized as important nutrient signaling mediators. As both SIRT1 and AMPK have been demonstrated to involve in circadian control, the findings suggested that proper coupling of circadian rhythm to metabolic flux is key to ameliorate disorder progression. We will study the hypothesis through the following approaches:
1. Use circadian disruption methods, including sleep disruption and genetic mutants of circadian components, to establish the link between circadian dysfunction and neurodegenerative progression.
2. Use longevity models, e.g., Sirtuins and AMPK strains, to follow the activities in coupling metabolic and circadian control. We will further investigate if the activities could amend neurological disorders.
3. Study the role of SCN in executing spatial and temporal oscillations. We will follow the signaling cascades and a number of key transcriptional regulators to explain the underling mechanisms. The answers may be valuable to address the age-related circadian decay process, and the temporal organization of circadian behavior in vivo.