This is a resubmission for an ADAMHA Scientist Development Award for Clinicians. During the period of the award, a principal career development activity will be to develop proficiency in tissue RNA extraction, agarose gel electrophoresis and Northern hybridization as they are applied to the study of the molecular basis of lithium's action. Despite its long-standing clinical use and efficacy in the treatment of recurrent mood disorders and extensive investigations into the mechanism of its action, there is no consensus concerning the major target of lithium's therapeutic effect. An understanding of the molecular basis of lithium's action may enhance our understanding of the molecular and genetic basis of bipolar affective disorder and recurrent unipolar depression. Since second messengers couple neurotransmitters and neuropeptides to the expression of transcription factors, we have been interested in the possibility that lithium may influence gene expression. In particular, we have focused our attention on the fos protooncogene since it is regulated by both the cyclic nucleotide and phosphoinositol (PI) pathways. Ongoing work in our lab suggests that lithium augments fos expression induced by agonists that stimulate protein kinase C (PKC). Since fos is a component of the AP-1 transcription factor, enhanced expression by lithium could have widespread effects on gene expression in the brain. Recent, preliminary studies in our lab indicate that lithium inhibits the expression of corticosterone (CORT) induced neuropeptide Y (NPY) and enkephalin (enk) gene expression. In an animal model of depression, """"""""learned helplessness"""""""" (LH), Henn and colleagues have found the density of hippocampal glucocorticoid (GC) receptors to be reduced in rats from a selection inbreeding colony taken to the eleventh generation, by comparison to a control, non-learned helpless (NLH) group. Glucocorticoids regulate several, perhaps many, genes governing neurotransmitter and neuropeptide synthesis. An effect of lithium on genes co-regulated by glucocorticoids and AP-1 may be relevant to understanding its therapeutic effectiveness and provide insight into the molecular basis of mood disorders. The candidate is interested in studying the effect of lithium on GC-stimulated neuropeptide Y and enkephalin gene expression in the brain, and to examine the consequences of reduced GC receptors in the CORT induction of NPY and enkephalin gene expression in LH animals.
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