Development of a patient derived cellular model of circadian disruption in bipolar disorder

Sleep and circadian rhythm disruption (SCRD) are now recognized to be common comorbidities in patients suffering from bipolar disorder. Examples include SCRD in patients with bipolar disorder as well as associated animal models of neuropsychiatric disorders and conversely, psychiatric phenotypes in mouse models with clock mutations. Although SCRD is invariably associated with neuropsychiatric illness, SCRD is rarely treated, as there are very few treatment options. Moreover, there is emerging evidence that addressing SCRD in individuals with psychiatric disorders may also have positive effects on their symptoms. In order to address this need,we are interested in the development of drugs that modulate circadian rhythms. To this end, we need suitable system to model SCRD at the in vitro level. Here, we propose to develop a cellular model derived from bipolar patient fibroblasts that faithfully represent the endogenous rhythm. This in vitro correlate of SCRD will be highly informative on endogenous clock deficits in bipolar disease. Further, this will provide a robust cell-based model of SCRD that can replace a large number of animal models, that are the only currently available alternative. We will test drugs known to alter circadian rhythms on our patient-derived fibroblast model and have an effect on mood (e.g. lithium) and test the predictive capacity of our model to find drugs that modulate circadian rhythms and thereby mood. Our work will have the following impacts:

1. Studying the rhythms from patient derived fibroblasts would inform us of the clock deficits and provide us with molecular targets for drug discovery and potentially new drugs from our drug screen.
2. Using patient-derived cells would significantly reduce the use of rodents including transgenic mice to model circadian rhythm deficits in mood disorders by replacing it with a relevant human model.
3. This model, if successful, could be extended to awide range of conditions that are comorbid with SCRD.