The discovery of Growth Hormone Secretagogues (GHS) has expanded our understanding of the regulation of Growth Hormone (GH) secretion. Although the receptor for these GHS has been identified, the endogenous ligand(s) remains unknown. We hypothesize that a second peptide derived from the carboxyl- terminal end of the GHRH gene is an endogenous GHS ligand. This newly discovered peptide, GHRH Related Peptide (GHRH-RP) is found in the brain and the testes. A biologic action for testicular GHRH-RP has been identified, but GHRH-RP's action in the brain is not yet understood. This project is expected to expand our knowledge of the complex regulation of the growth hormone axis. Although it is designed as a basic research project, it has important implications for clinical research. The diagnostic evaluation and intervention strategies available for children with growth abnormalities could be advanced by the data generated. Our hypothesis will be tested in the following manner: 1. a. We will determine whether GHRH-RP acts to regulate GH production and release in vitro using primary anterior pituitary cell cultures. The effects of GHRH-RP treatment on the level of expression of GH, the GHS receptor, ACTH, TSH, prolactin, LH, FSH levels will also be measured. b. We will examine the second messenger systems activated by GHRH-RP including the PKC and PKA pathways. 2. We will characterize the in vivo CNS effects of GHRH-RP. a. Direct intracerebroventricular administration of GHRH-RP antisera into the rat brain will be performed and the effects on changes in growth, behavior, fertility and feeding patterns will be determined. b. The in vivo effect of GHRH-RP on hypothalamic expression of the GHS receptor and somatostatin will be assessed. Other factors including GH, prolactin, ACTH, TSH, prolactin, LH and FSH levels will also be evaluated.
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