Bipolar affective disorder is a severe, chronic and disabling illness which affects 1.2% of the population (lifetime prevalence) and is a leading cause of hospitalization. Approximately 25% of affected people attempt suicide. After more than two decades since the discovery of lithium's efficacy as a mood-stabilizer, it continues to be the treatment of choice for this condition. However, although it has revolutionized the treatment of bipolar disorder and remains one of psychiatry's most important therapies, recent evidence indicates that 20-40% of all patients fail to show an adequate antimanic response to lithium. There is currently no information about the genetic or biochemical factors associated with lithium responsiveness or resistance. Furthermore, the biochemical basis for lithium's mood-stabilizing actions remains to be fully elucidated. Although there is now considerable evidence that lithium affects the phosphoinositide second messenger signal transduction system, the connection between these effects and the therapeutic effects of lithium has not been fully established. This proposal is directed at determining the molecular mechanism of lithium's actions and the genetic and biochemical basis for responsiveness to lithium. The genetic potential of yeast will be exploited to accomplish this, as yeast is the only eukaryote in which genetic analysis can be easily applied to identify lithium's targets directly. In addition, it is the eukaryote most amenable to a combined genetic, biochemical, and molecular approach to characterize lithium targets. The recent determination of the sequence of the entire yeast genome has contributed greatly to the genetic and molecular potential of the yeast model system. The goal of the proposed experiments is to identify lithium target genes and to determine how these genes affect inositol metabolism.
The specific aims are: (1) To determine the effects of lithium on inositol metabolism. This will involve characterizing the effects of lithium on the known components of inositol metabolism and will result in identification of lithium targets among genes known to be involved in this pathway. (2) To identify new lithium target genes using unbiased genetic screens. Genes not previously known to be involved in inositol metabolism, such as regulatory genes, will be identified by genetic screens based on altered sensitivity to lithium. (3) To characterize the functions of lithium target genes identified in the first two aims. The target genes will be cloned and characterized by genetic and molecular techniques to address the following questions: What are the gene products? How are they affected by lithium? How do these genes control inositol metabolism? Ultimately, an understanding of target gene function should improve the prospects for the development of more effective long-term treatment regimens, and for the identification of biochemical and/or genetic predictors of lithium responsiveness.
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