Reactivating Circadian Rhythms as a Therapeutic Strategy: Insights from Basic Research 

 

Masao Doi, Ph.D.

Professor, Graduate School of Pharmaceutical Sciences,

Kyoto University

 

One of the most significant conceptual changes brought about by the discovery of clock genes and development of circadian-clock mutant mice is the recognition that impaired circadian rhythmicity extends its impact beyond sleep, driving pathogenesis of a wide variety of disorders such as cancer, obesity, and hypertension. However, despite this growing clinical evidence, chronobiology still lacks a coherent answer to the converse question: can restoration of circadian rhythms ameliorate—or even reverse—such diseases? Here, in my talk, three complementary pharmacological strategies—each still in preclinical development—will be explored. First, direct modulation of the transcription-translation feedback loop (TTFL)—the core gene-regulatory circuit that generates 24-hour rhythms in almost all nucleated cells—is reviewed as an approach to manipulation of cellular circadian biology. Second, the suprachiasmatic nucleus (SCN)-enriched G-protein-coupled receptor Gpr176 is highlighted as a central-clock target, given its ligand-independent, Gz-mediated control of cAMP signaling and demonstrated ability to reset the master pacemaker. Third, the concept of rhythmic enhancement of output function is introduced and exemplified by describing re-activation of circadian NAD⁺-dependent 3β-HSD activity in the meibomian gland—using nicotinamide mononucleotide (NMN)—to restore peripheral clock-driven steroidogenesis in this tissue, which leads to amelioration of meibomian gland dysfunction, a leading cause of dry eye disease. In my talk, I will highlight the molecular logic of each strategy; both mechanistic insights and safety-efficacy considerations will be discussed. 

 

References

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Miyake et al., Size-reduced DREADD derivatives for AAV-assisted multimodal chemogenetic control of neuronal activity and behavior. Cell Rep Methods 4, 100881 (2024)

 

Miyake et al., Minimal upstream reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm. Cell Rep. 42, 112157 (2023)

 

Sasaki et al., Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction. Nat Aging 2, 105-114 (2022)

 

Doi et al., Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity. Nat Commun 10, 2563 (2019)

 

Doi et al., Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour. Nat Commun 7, 10583 (2016)