Catecholamine neurotransmitters have been implicated in the pathophysiology of several neurological and psychiatric disorders such as schizophrenia, depressive illness and Parkinson's disease. The enzyme which catalyzes the first and rate limiting step in the biosynthetic pathway of catecholamine neurotransmitters is tyrosine hydroxylase (TH) and its gene expression is limited to catecholaminergic neurons. In this proposal, human neuroblastoma cell lines which are either adrenergic (TH-expressing) or cholinergic (TH-nonexpressing) will serve as the model system. The molecular events and factors governing this differential expression of the TH gene will be investigated. In order to gain a deeper understanding of gene regulation in the nervous system, it is of critical importance to define which nuclear proteins (trans-acting elements) specifically bind to the promoter DNA sequences (cis-acting elements). Characterization of the molecular interactions between trans-acting and cis-acting elements should lead to the successful isolation of the gene(s) for the relevant trans-acting factor(s). As an extension of these studies, tissue-specific expression will further be investigated in transgenic mouse models. The results from these studies may provide insights not only into the regulation of catecholamines in general but also into the etiology of some human brain disorders that exhibit altered catecholamine expression.
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