MOLECULAR BIOLOGY OF CATECHOLAMINE SYNTHESIS IN STRESS

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Stress plays a significant role in the development of so called diseases from civilization -- cardiovascular diseases, mental disorders, gastrointestinal disorders -- and facilitates the development of immune diseases and cancer. The sympathoadrenal system, which produces the catecholamines, norepinephrine and epinephrine, is one of the first systems activated in an organism during stress. Earlier studies by R. Kvetnansky and coworkers, showed that chronic cold and repeated immobilization stress elicited a large rise in circulating catecholamines, as well as an increase in adrenal activities of the catecholamine biosynthetic enzymes, particularly tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Recently we have begun to study changes in expression of the genes for these enzymes with stress. Immobilization stress was found to markedly elevate TH and DBH mRNA levels. Moreover, there was a striking difference in the response to a single versus repeated stress. This project will enable us to further delineate the changes in expression of catecholamine biosynthetic enzymes in stress. Specifically it will: I.Study differences between a single and repeated stress. For example, we will determine what is the minimum time of stress required to elicit changes in gene expression, as well as how much is required for the single stress to be "remembered" as determined by an altered response to a second stress. II.Ascertain the transcription factors involved in regulation of the expression of TH and DBH genes during a single and repeated immobilization stress. III.Study the involvement of neural and humoral factors, and specifically neuropeptides, in the regulation of gene expression of catecholamine biosynthetic enzymes in stress. IV.Ascertain if female Sprague Dawley rats respond to stress similarly to the response found in males. The results of this study should contribute to a new understanding of the molecular biological basis of activation of the sympathoadrenal system in stress.