The long-term objectives of this proposal are to understand the normal physiological roles of the natriuretic peptides and their mechanisms of signal transduction.
The specific aims are: 1. To test whether BNP and CNP, as well as ANP, inhibit ACTH secretion by pituitary cells and to determine the localization of ANP, BNP, and CNP in the hypothalamus. 2. To determine with natriuretic peptide receptors are expressed in corticotrophs; to test whether inhibition of ACTH secretion by natriuretic peptides is mediated by cyclic GMP, and if so, through what pathway. 3. To test the physiological importance of natriuretic peptides in regulating ACTH secretion by using dominant negative mutants to ablate corticotroph natriuretic peptide receptor function in transgenic mice. The health-relatedness of the project is in leading to a better understanding of the mechanisms of action and normal physiological roles of peptides that are important in regulating the stress response. The experimental plan is: 1. To test which natriuretic peptides inhibit ACTH secretion by cultured pituitary cells as measured by radioimmunoassay, and to use immunohistochemistry to determine the location of the inhibitory natriuretic peptides in the appropriate regions of the hypothalamus; 2. To use immunohistochemistry to determine the distribution of cyclic GMP-coupled and non-cyclic-GMP-coupled receptors for natriuretic peptides in corticotrophs; to test the ability of cyclic GMP-coupled natriuretic peptide analogues to inhibit ACTH secretion. To measure natriuretic peptide effects on cyclic GMP and cyclic AMP levels in corticotrophs. To test the ability of cyclic GMP analogues to inhibit ACTH secretion and to activate cation channel in corticotrophs. 3. To prepare transgenic mice expressing a truncated, epitope-tagged ANP receptor under the control of the POMC promoter; responses of these mice to stress will be compared with those of control mice.
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