Imbalances in brain catecholamine (CA) neurotransmitter systems are associated with aging as well as a whole array of debilitating neurological ad psychiatric disorders; including Parkinson's disease, Alzheimer's disease, Tourette's syndrome, manic-depressive illness and schizophrenia. These ailments serve to underscore the critical importance that Cas play in the proper functioning of the brain. The availability of CA neurotransmitters is largely determined by regulation of the rate-limiting enzyme, tyrosine hydroxylase (TH). Over the last nine years, studies from this laboratory have focused on identifying the genetic and epigenetic agents which regulate the first expression of the TH gene in the hope of discovering ways in which to manipulate its expression. We have taken advantage of the fact that the GABergic neurons of the striatum are phenotypically plastic for a time in their development. We discovered that, during this brief window, neurons can trans-differentiate into TH-expressing and DA-producing cells if exposed to the synergistic interaction of specific growth factors (aFGF, bFGF, BDNF) and an obligatory co-activating molecule (CA neurotransmitters, protein kinase A and C pathway activators). Our most recent studies have begun to explore precisely how these substances trigger expression of the TH gene. Thus far, one key pathway followed by these signals is through MAP kinase to the AP-1 site on the 5' flanking region of the TH gene. Our proposed project aims are: 1) identification of known and new cis-and trans-acint factors; 2) the signal transudction pathways that lead to their activation of the TH gene; 3) the celluar/molecular changes which repress TH induction later in life and 4)finally, whether the differentiation of other neurotransmitter phenotypes can be similarly regulated. The long range goal of this work is to elucidate the cellular and molecular processes regulating neurotransmitter synthesis so that brain cells can someday be engineering or stem cells can be stimulated to produce more or less of the appropriate neurotransmitters in the damaged, diseased or aging brain.
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