The long range goal of this research is to understand the role of the brain in the regulation of growth. A variety of common metablic disorders, such as diabetes mellitus, malnutrition, and obesity, are accompanied by growth deficiencies thought to be associated with abnormal secretion of insulin-like growth factor-I (IGF-I) by the liver. An unsolved problem is how IGF-I inhibits the secretion of GH by a feedback mechanism operating in the brain. IGF-I inhibits GH secretion by acting directly on the pituitary gland, but evidence indicates that this negative feedback operates also at the level of the hypothalamus, where it is thought to stimulate the release of the GH inhibitory hormone, somatostatin (or somatotropin release inhibitory factor, SRIF). The mechanism involved in the regulation of GH secretion by IGF-I at the level of the brain is unknown, however. Recent data indicating that IGF-I receptors are present in the median eminence (ME) raises the hypothesis: IGF-I receptors inthe ME regulate SRIF secretion into the hypophyseal portal blood in the ME. The proposed experiments are designed to investigate three specific aims that address this hypothesis: (1) To determine if IGF-I receptors are located on the terminals of axons containing SRIF in the ME; (2) To determine if IGF-I receptors in the ME become more numerous (upregulate) in association with metabolic conditions accompanied by low plasma IGF-I levels; (3) To determine if regulation of IGF-I receptors in the ME changes the senitivity of SRIF release to IGF- I. The method used to measure binding of labeled IGF-I in the ME will be quantitative autoradiography (QAR): (a) microscopic quantitation of autoradiographic grain density in the ME after in vivo injection of labeled IGF-I into plasma; (b) computer image analysis of autoradiographic images of rat brain images on LKB film, produced by in vitro labeling of brain slices with labeled IGF-I. Binding sites for IGF-I (and the related peptide, IGF-II) in the ME and brain will be measured and characterized by QAR to determine specficity for IGF's analogues and verify receptor status, and to determine if ME IGF-I receptors undergo homeostatic changes in binding. Blood from the ME will be collected in experiments designed to test whether changes in ME IGF-I receptors are associated with increased sensitivity of ME SRIF release to plasma IGF-I levels. These results will support the hypothesis that IGF-I interacts with IGF-I receptors in the ME to control the release of SRIF into hypophyseal portal blood.
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