The broad objective of this proposal is to investigate the hypothalamic mechanisms which mediate the ultrashort-loop feedback (autoinhibition) and reciprocal regulation of growth hormone- releasing factor (GRF) and somatostatin (somatotropin release- inhibiting factor, SRIF), and to observe how such systems of hypothalamic regulation influence pulsatile growth hormone (GH) secretion. The reason for investigating hypothalamic GRF and SRIF selfregulating systems is because disruption of these mechanisms may contribute to the pathogenesis of dwarfism, gigantism, acromegaly, and pituitary tumor formation in humans.
The specific aims proposed to investigate the mechanisms of GRF and SRIF ultrashort-loop feedback are: 1. to characterize further the mode by which intrahypothalamic SRIF produces its ultrashort-loop feedback effect in vivo through the use of GRF and SRIF peptide antagonists; 2. to examine the possible physiological participation of GABA neurons (interneurons?) in mediating GRF and SRIF ultrashort-loop feedback in vivo; 3. to obtain in vitro correlates concerning the role of GABA in mediating GRF and SRIF ultrashort-loop feedback; 4. to detect and measure GRF receptor activity which may mediate GRF ultrashort-loop feedback in the hypothalamus; 5. to determine whether hypothalamic GRF receptor characteristics are altered by various pharmacological or physiological states as they relate to modulation of GRF autofeedback.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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Georgetown University
School of Medicine & Dentistry
United States
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Mulroney, S E; McDonnell, K J; Pert, C B et al. (1998) HIV gp120 inhibits the somatotropic axis: a possible GH-releasing hormone receptor mechanism for the pathogenesis of AIDS wasting. Proc Natl Acad Sci U S A 95:1927-32
Peisen, J N; McDonnell, K J; Mulroney, S E et al. (1995) Endotoxin-induced suppression of the somatotropic axis is mediated by interleukin-1 beta and corticotropin-releasing factor in the juvenile rat. Endocrinology 136:3378-90
Haramati, A; Lumpkin, M D; Mulroney, S E (1994) Early increase in pulsatile growth hormone release after unilateral nephrectomy in adult rats. Am J Physiol 266:F628-32
Mulroney, S E; Lumpkin, M D; Roberts Jr, C T et al. (1992) Effect of a growth hormone-releasing factor antagonist on compensatory renal growth, insulin-like growth factor-I (IGF-I), and IGF-I receptor gene expression after unilateral nephrectomy in immature rats. Endocrinology 130:2697-702
Mulroney, S E; Lumpkin, M D; Haramati, A (1991) Suppression of growth hormone release restores phosphaturic response to PTH in immature rats. Am J Physiol 261:F1110-3
Lumpkin, M D; McDonald, J K (1989) Blockade of growth hormone-releasing factor (GRF) activity in the pituitary and hypothalamus of the conscious rat with a peptidic GRF antagonist. Endocrinology 124:1522-31
McDonald, J K; Lumpkin, M D; DePaolo, L V (1989) Neuropeptide-Y suppresses pulsatile secretion of luteinizing hormone in ovariectomized rats: possible site of action. Endocrinology 125:186-91
Mulroney, S E; Lumpkin, M D; Haramati, A (1989) Antagonist to GH-releasing factor inhibits growth and renal Pi reabsorption in immature rats. Am J Physiol 257:F29-34
Lumpkin, M D; Mulroney, S E; Haramati, A (1989) Inhibition of pulsatile growth hormone (GH) secretion and somatic growth in immature rats with a synthetic GH-releasing factor antagonist. Endocrinology 124:1154-9