This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Bipolar disorder, a common psychiatric disorder, is characterized by recurrent episodes of mania and depression. The mood stabilizer lithium has proven its efficacy in preventing the recurrence of mania and suicide more than any other drug for more than 50 years. In the past decade, however, lithium use in the United States has declined substantially because lithium is more difficult to use and has a low margin of safety. Only a subpopulation of bipolar patients shows benefits from lithium treatment. To improve lithium pharmacotherapy, it is beneficial to develop an in vitro assay that can be applied prior to treating patients with the drug to predict which patients will show a therapeutic response to lithium. The assay can also be used to find drugs that are as effective as lithium, applicable to all types of bipolar patients, and with fewer side effects. Because there is no cell or animal model to study differential lithium sensitivity, such assay can be used as a model to understand mechanisms how such sensitivity is controlled. Recent studies indicate that multiple genes and proteins cooperate to control pathogenesis of bipolar disorder and lithium sensitivity. Therefore, testing for differential lithium responsiveness utilizing more comprehensive parameters should be more successful in predicting lithium sensitivity. Two parameters are chosen to compare lithium sensitivity;in vitro measurements of circadian phase and peroxiredoxin 2 (PRD2) in blood cells. There is a close relation between mood status and circadian rhythm expression, and lithium has been shown to affect circadian rhythm expresion in many species, including humans. Therefore, circadain parameter is one of the promising output to evaluate the effects of lithium on moode stabilization. Another line of study has shown that bipoalr patients have neurodegenration in their brains, and lithium can fix such conditiosn. Our previous R-Center supported project identified PRD2 as a single gene that was affected by lithium stimulation. Considering PRD2'neuroprotective roles, it would be worth evaluating the effects of lithium on this gene expression between lithium responders and non-responders. In this proposal, lithium responses in these parameters will be correlated to test the hypothesis that lithium differentially affects circadian phase and PRD2 levels in macrophages of lithium-responsive and lithium-insensitive patients.
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