Growth hormone releasing factor (GRF) stimulates growth hormone (GH) in all species tested. Our ultimate objective is to define the physiologic role of GRF and to understand the molecular mechanisms involved in its mechanism(s) of action. Therapy of GH deficiency with GRF is being studied with the goal of devising a simple, safe and effective therapy for children with short stature secondary to GH deficiency. Our approach combines both clinical and basis studies (e.g., observation of pancreatic tumor secreting GRF being translated into the demonstration of GRF biological activity in the tumor; delivery of that tumor to laboratories at The Salk Institute for isolation, characterization, and peptide sequencing; subsequent use of synthesized GRF for diagnostic and therapeutic purposes). The CLINICAL STUDIES will: (a) define the factors which are involved directly or indirectly in the control of pulsatile secretion of GH. Specific factors to be examined include age, gender, gonadal steroid and glucocorticoid environments, interaction with nutrition, sleep, exercise, beta adrenergic and dopaminergic systems, and effects of (recombinant) somatomedin C (IGF-1) administration; (b) determine the effects of alternative stimuli of GH release on GRF-stimulated GH secretion in normal man. Whether L-Dopa, clonidine and arginine increase GH release by stimulating endogenous GRF or suppressing somatostatin secretion will be assessed; (c) explore alternate modalities of treatment with GRF utilizing various regimens (e.g., q 3 hourly vs. BID and subcutaneous vs. intranasal administration), analogues and formulations. The BASIC SCIENCE STUDIES will: (a) establish the importance of cyclic AMP in the mechanism of action of GRF; (b) determine the involvement of phospholipids and arachidonate and its metabolites on GRF-mediated GH release; (c) describe and identify proteins phosphorylated or dephosphorylated by GRF; (d) determine the effects of sex steroids and aging on somatotroph number and secretory function; and (e) define the optimal hormonal conditions for maintaining and increasing pulsatile GH release in vitro. In this way, the role of GRF, somatostatin, and IGF-I on GH release can more precisely be defined and the testing of novel GRF agonists conducted. Information thus obtained will then be used to optimize clinical protocols.
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