This is a proposal to study the regulation and actions of hypophysiotropic factors for growth hormone (GH) and prolactin (PRL) and their role in clinical disorders of GH and PRL secretion which represents a continuation of the long-standing goals of this laboratory. The identification and synthesis of human (ectopic) GH-releasing factor (GRF) has led to an exciting new era of investigation. Effects of GRF alone and in combination with other hormonal and metabolic agents will be studied after injection or infusion in normal subjects and in patients with disorders of GH secretion (acromegaly, anorexia nervosa, diabetes, idiopathic GH deficiency). The studies will define physiologic control mechanisms in the normals and identify pathophysiologic mechanisms in patients with neuroendocrine disorders. Distribution of GRF in the central nervous system, extraneural tissue, and tumors and measurement of GRF in plasma, after appropriate validation, will be performed using a recently established radioimmunoassay. Plasma measurements during infusion of exogenous GRF will be used for assessing metabolic clearance and secretion rates of the releasing hormone. Physiologic regulation of GRF in the rat will be studied in vitro (hypothalamic incubations) and in vivo (push-pull cannulae) using a RIA for rat GRF. A heterologous system will initially be used until rat GRF becomes available. Measurements of GRF and somatostatin (SRIF) will be used to study the integration of the regulation of GH secretion with particular emphasis on feedback effects of GH and somatomedin-C, thyroid hormone, corticosterone, estrogen, and potential neuropeptidergic and -aminergic transmitters. The role of membrane receptors in modulating the effects of GRF and SRIF on the somatotroph will be determined. An attempt will be made to develop a hybrid cell line of a human GRF-secreting tumor to study the cellular biology of GRF in tissue culture. The role of circulating dopamine antagonists in dopaminergic regulation of PRL secretion in hyperprolactinemic states will be studied using pituitary cell cultures as a bioassay system. An experimental model for the hyperprolactinemia of chronic renal failure will be developed in the rat and used to identify the site of the abnormality responsible for dopamine resistance and the mechanisms involved. The results of these studies will provide a better understanding of the role of the CNS in clinical disorders of GH and PRL secretion and may ultimately lead to new therapeutic approaches.
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