Vasopressin (VP) is a nonapeptide hypothalamic hormone released into the peripheral circulation in response to hyperosmolality, hypotension, hypovolemia, and other stresses. Its major functions in man include the maintenance of normal plasma osmalality, blood pressure, and blood volume. In addition, it regulation is abnormal in several pathologic states, including congestive heart failure, chronic pulmonary disease, and chronic liver disease. Despite these critically important roles, very little is known regarding the nature of those factors which regulate the expression of the VP gene, largely due to a lack of suitable in vivo and in vitro models. The overall goal of this proposal is to identify in rats both the factors which regulate the biosynthesis of VP via effects upon VP gene expression, as well as the mechanisms by which these factors exert their effects. Endocrine and environmental stimuli to be studied include hyperosmolality, hypovolemia, glucocortocoid deficiency, and environmental stress. Also to be investigated will be neurotransmitters and neuromodulators postulated to regulate the VP gene. We will determine: 1) which of these stimuli result in elevated levels of hypothalamic VP mRNA 2) whether or not these increased mRNA levels are due to increased transcription of the VP gene, increased stability of VP mRNA, or to both factors 3) the relationship among the stimulation of VP secretion, the intracellular VP peptide content and the activation of VP gene expression 4) whether intracellular VP content, acting via end-product inhibition of the VP gene, plays an important role in VP gene expression 5) the role of VP mRNA poly A tail length in the regulation of VP genes expression, and 6) whether the vasopressin- deficient Brattleboro rat has a specific regulatory defect in VP gene expression separate from the known structural defect in the VP gene. All of the above will be investigated using: a) intact animals b) primary dispersed cultures of fetal rat hypothalamic cells and c) heterologous cell lines into which the VP gene has been transfected. Answers to these questions, obtained using these several interrelated approaches, should provide important clues to both normal and disordered states of VP gene regulation.
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