Bipolar affective disorder is a severe, chronic and disabling illness that affects 1-2 percent of the population and is a leading cause of hospitalization. Recurring bouts of mania and depression devastate family relationships and impair career progress. Approximately 15 percent of affected people commit suicide. Only two drugs are currently approved by the FDA for treatment of this disorder, lithium and valproate. While lithium has revolutionized the treatment of bipolar disorder and remains one of psychiatry's most important therapies, 20-40 percent of all patients fail to show an adequate antimanic response to lithium. Similarly, valproate has limited efficacy. There is evidence that lithium and/or valproate affect the phosphoinositide second messenger signal transduction system, protein kinase C, glycogen synthase kinase, transcription activation by AP-1, and B-cell Iymphoma protein 2 (bc1-2). However, the therapeutic mechanisms of action of these drugs have not been elucidated. Although lithium and valproate are structurally dissimilar and may not exert their effects in exactly the same manner, identification of genes regulated by both drugs may provide insight into common mechanisms of action. We are utilizing the yeast model system to elucidate molecular mechanisms of action common to lithium and valproate. Yeast is currently the only eukaryote in which we can combine genetic, molecular, and functional genomic approaches to identify lithium and VPA targets. We have identified genes that are affected by both lithium and valproate in pathways for phosphoinositide metabolism (INOI and IN02), secretion and exocytosis (SEC14 and SCS2), fatty acid metabolism (PDC5), and transcription activation (DOT6). The goal of the proposed experiments is to determine how lithium and valproate affect activity and expression of these genes.
The specific aims are: 1) Targets in inositol metabolic pathway: Determine how lithium and valproate affect expression of INOI and other genes regulated by the transcriptional activator IN02. 2) Targets in other pathways that are affected by inositol: Characterize lithium and valproate targets in secretion, the unfolded protein response, fatty acid synthesis and transcription activation. 3) Targets not affected by inositol: Genome-wide expression analysis to identify all yeast genes regulated by lithium and valproate. Ultimately, an understanding of target gene function may provide insight into the molecular basis of the disease process, and may assist in the identification of biochemical and/or genetic predictors of drug responsiveness. The yeast model system may also be utilized in future testing of safer and more effective treatments.
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