A significant investment of research resources over the past 25 years has fruitfully demonstrated the role of CNS peptides in physiological regulation, behavior, and pathological states. In spite of their recognized importance in health and disease, comparatively little work has been devoted to establishing the molecular mechanisms that regulate neuropeptide synthesis. Since this information is crucial for understanding their participation in biological functions, the long-term objective of this proposal is to further our knowledge of the molecular mechanisms that control the transcription of neuropeptide genes. This project will focus upon the regulation of four neuropeptides: vasopressin oxytocin, cholecystokinin, and galanin, in the hypothalamo- neurohypophysial system (NHS) of the CNS. The NHS is an ideal experimental model system for determining the transcriptional regulation of the aforementioned genes. It is of great importance in neuroendocrine and behavior function (anti-diuresis, blood pressure control, stress, parturition, lactation, and maternal behaviors), and these neurons exhibit a very dramatic response to stimulation. Using the laboratory rat, investigations show that changes in body water balance, by maintenance on drinking solutions of salt water or injection of hypertonic saline, causes NHS neurons to release all four neuropeptides and alter their 'rate' of peptide synthesis, manifested by increases in messenger RNA levels. In this project, the focus will be upon the basic leucine zipper family of transcription factors (bZips, including the factors Fos, Jun an CREB). Based upon the hypothesis that bZip transcription factors play a role in regulating the transcription of NHS neuropeptides, this research will: 1) demonstrate by in situ hybridization of vasopressin, oxytocin, galanin and cholecystokinin genes, 2) show by mobility shift DNA-binding assays that there are specific DNA sequence in the promoter regions of these neuropeptide genes that interact with bZip transcription factors, and 3) demonstrate with in vitro transfection of promoter sequences in cultured neural cells, that these sequences are crucial for the control of neuropeptide gene transcription. What is discovered using the NHS as a model system will have relevance to gene regulation of these important peptides in neuroendocrine function as well as in other neural systems of the CNS, where a wide range of neurological, endocrinological and immunological functions are attributed to these neuroactive substances.
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