Science

Circadian Rhythm

Your body’s internal clock is a time-keeping system that generates 24-hour rhythms in behavior and physiology in tune with day-night cycle. Core-clock proteins are found throughout the body and maintain rhythms in metabolism, blood pressure, immune function, the cardiovascular system, central nervous system function, and myriad other processes.  Clock dysregulation, for example from shift work, results in a broad range of diseases such as cancer and metabolic syndrome.

Synchronicity Pharma is focused on developing drugs that address this dysregulation, thereby stopping or reversing the course of the circadian rhythm associated diseases.

 

Circadian Rhythm’s Role in Disease

For decades, the correlation between circadian dysfunction, particularly sleep disruption, and a broad range of diseases has been established1,2. More recently, the details of the mammalian core-clock mechanism were established, much of this by our founders. Further, they and others showed that the clock runs in most human cells, including the brain, but also in peripheral organs like the liver, skeletal muscle, and the lungs. The role of the clock in these peripheral organs and its importance to health is only beginning to be appreciated.

The 2017 Nobel Prize in Physiology and Medicine recognized advances in the understanding of the circadian clock mechanism. This research has begun to reveal the stunning breadth of clock-controlled-gene expression, unique in our different tissues, and to elucidate the roles of these rhythmic cycles in health and disease in humans.

Disease areas now linked to circadian dysfunctions include:

  • Oncology
  • Metabolic and endocrine disorders
  • Inflammatory and autoimmune disease
  • CNS disorders

 

Core-Clock Proteins

The core circadian clock is a 24-hour transcriptional/translational feedback loop in which the core clock activators, BMAL1 and CLOCK/NPAS2, regulate the cyclic expression of two repressors families, the Period (PER1-3) and Cryptochrome (CRY1-2) genes. Further fine tuning is afforded by the ROR/REV-ERB feedback loop, as shown below3.

 

 

These core-clock proteins and the associated cycle are present in most, if not all, of the cells in the human body.  Although the core-clock machinery is present in all cell types, the genes that they influence, known as clock-controlled genes, are tissue specific.  About 50% of genes are regulated by the core-clock in humans and mice, providing a mechanistic link from the clock to the many normal and diseased-associated physiological processes.

 

References:

  1. Anafi et al. “CYCLOPS reveals human transcriptional rhythms in health and disease” PNAS (2014) 111:16219
  2. Chen et al. “Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems” Ann. Rev. Pharmacol. Toxicol. (2018) 58:231
  3. Gaucher, J. et al. “Molecular Cogs: Interplay between Circadian Clock and Cell Cycle” Trends Cell Biol. (2018) 5:368