STRESS INDUCED CHANGES IN GENE EXPRESSION

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Stress play a significant role in the development of cardiovascular diseases (hypertension, heart attack), mental diseases (depression, schizophrenia), gastrointestinal disorders (stomach ulcers) and also plays a permissive role in development of immune diseases and in cancer. Stress related disorders are estimated, besides the human suffering, to cost roughly $300 billion annually and comprise nearly two-thirds of the ailments seen in doctors' offices. The sympathoadrenal system is one of the first systems activated during stress. Despite much work on the physiology of stress little is known regarding the molecular changes in gene expression in stress. Our recent studies indicate that there are large changes in gene expression for the adrenal catecholamine biosynthetic enzymes with relatively short intervals of immobilization stress. The long term objective is to determine how genes are regulated under stress in order to find preventive or curative measures. The central hypothesis to be tested in this proposal is that the expression of catecholamine biosynthetic enzymes is modulated by stress. Specifically: 1. Test the hypothesis that neuronal and humoral factors activated during stress influence the over expression of the adrenomedullary catecholamine biosynthetic pathway in response to stress. 2. Test the hypothesis that the stress-elicited changes in gene expression involve transcription activation of genes for the catecholamine biosynthetic enzymes by several transacting factors. 3. Test the hypothesis that a single and repeated immobilization stress elicits increased gene expression of catecholamine biosynthesis enzymes in the sympathetic ganglia, the major contributor to circulating norepinephrine. A better understanding of the mechanism of stress, should be very helpful in ultimately designing medications to protect the individual from such damage, particularly when expected to be exposed to chronic or repeated stress. It will also lead to a better understanding of the dangers of various degrees of stress and how to alleviate these dangers.