A human pancreatic growth hormone releasing factor (hpGRF) has been extracted and sequenced from a pancreatic tumor from one of our patients with acromegaly. The proposed studies will characterize the clinical pharmacology of this hpGRF and begin to determine its mechanism of action in stimulating GH biosynthesis and release. Clinical studies in man: Study I will assess the safety, clinical effects, hormonal specificity, and dose response relationship of hpGRF in man; Study II will determine the efficacy of infusions of hpGRF on GH release in normals and assess interactions of hpGRF with TRH, dopamine, glucose clamp, and somatostatin; Study III will determine the usefulness of hpGRF tests in GH deficiency and excess states; Study IV will design a method for hpGRF therapy of GH deficiency and short stature; Study V will determine the role of hpGRF as a glucose-dependent insulinotropic hormone; in Study VI we will raise antibodies to hpGRF (a) for the development of hpGRF RIA and (b) as a probe for the basic science studies. The hpGRF levels will be measured in acromegalic patients to diagnose ectopic GRF secretion as cause of acromegaly and in normal subjects after exogenous hpGRF to determine its pharmacokinetics and the concentrations necessary to stimulate GH secretion. Basic studies will utilize in vitro techniques using dispersed rat anterior pituitary cells either in primary culture or under continuous perifusion to determine the time course, potency, and specificity of hpGRF at the anterior pituitary. Surveys of clonal GH cell lines will be performed for hpGRF receptor activity. We will characterize somatotroph hpGRF receptor transduction requirements and investigate the plasticity of hpGRF induced GH release. By using morphological techniques, quantitative ultrastructural and cellular correlates of hpGRF activity will be determined. We will develop an hpGRF receptor binding assay. The long-standing objectives are to determine for hpGRF: (1) its role in human physiology and pathophysiology; (2) its clinical pharmacology; (3) its utility as a test of pituitary GH reserve; (4) its clinical utility as therapy for GH deficiency in youth and in old age and also in children with short stature but normal GH reserve; and (5) its effects on pancreatic endocrine function and its relevance to disorders GH secretion in diabetes mellitus.
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