Researchers at the University of Memphis and University of Pennsylvania report the development of robust new liver and fat cell models that report circadian clock function. These models are amenable to high throughput drug screening and could be used to find promising small molecules to resynchronize or help body clocks function normally.
The consequences of modern life, eating and staying up later, shift work, cell phone addiction, and travel across time zones, all disturb internal clocks. These clocks are found in the brain where they regulate sleep, and also throughout the body, where they regulate much of our physiology and metabolism. Disrupting these clocks is called circadian misalignment which has been linked to metabolic problems even in healthy volunteers. These new cellular clock models could help scientists find new drugs that reset or help restore robust rhythms to metabolic clocks.
The study, Ramanathan et al., is published in the current issue of PLOS Genetics.
The scientists started with metabolically relevant cells -- hepatocytes and adipocytes -- representing major functions of the liver and adipose tissues, and thus important aspects of the body's energy processing and storing system. Then they genetically engineered them to flash light with a daily rhythm much like an alarm clock. They validated the cell models and showed that changing clock gene function in these cells is similar to what happens in mice lacking clock genes. "We are very excited about the prospect of using these more physiologically relevant cell-based models for gene and small molecule drug discoveries," says Dr. Andrew Liu, Assistant Professor of Biology at the University of Memphis.
These cellular clock models allow monitoring of molecular rhythms using inexpensive off-the-shelf recording devices, making it suitable for basic research laboratories, as well as large-scale screens in pharmaceutical companies. "The previous cellular models were great," says John Hogenesch, Professor of Pharmacology at the University of Pennsylvania Perelman School of Medicine, "but they needed high end imaging equipment that is out of reach for most labs and early stage startups." By expanding the number of labs that can do these studies, these models could catalyze better understanding of peripheral clocks as well as new genetic and chemical tools to improve their function.
- Chidambaram Ramanathan, Haiyan Xu, Sanjoy K. Khan, Yang Shen, Paula J. Gitis, David K. Welsh, John B. Hogenesch, Andrew C. Liu. Cell Type-Specific Functions of Period Genes Revealed by Novel Adipocyte and Hepatocyte Circadian Clock Models. PLoS Genetics, 2014; 10 (4): e1004244 DOI: 10.1371/journal.pgen.1004244
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