The goals of this proposal are to study the regulation of growth hormone (GH) secretion, the hypothalamic releasing and inhibiting hormones (GH-releasing hormone (GRH) and somatostatin (SRIF)) that control the secretion of GH, and to search for alterations in neuroendocrine function that may be responsible for disorders of GH secretion in man. The identification of each of the component hormones in this regulatory system (GRH, SRIF, GH, and insulin-like growth factor-l (IGF-l), the mediator of many of the growth promoting action of GH) and their molecular cloning allows for an integrated approach to the study of this hypothalamic-pituitary system that may serve as a model for other systems. The proposal will utilize techniques of molecular biology, cell culture, protein chemistry, in vivo measurements of hormone levels in hypophyseal portal blood, and clinical studies to study different aspects of this system. The regulation of hypothalamic GRH gene expression will be studied in vivo in response to hormonal and metabolic (starvation, diabetes, obesity) perturbations, and in vitro using GRH gene transfection. The conversion of the GRH precursor to the mature hormone will be studied in transgenic animals expressing the human GRH gene and the role of processing enzymes as potential regulators will be determined. The metabolism of GRH will be studied in circulation and at the sites of GRH action and the enzymes involved will be characterized. The neuroendocrine regulation of GRH and SRIF will be studied by direct measurements of the two neurohormones in portal plasma and in hypothalamic perfusate fluid of unanesthetized sheep and the molecular forms of each hormone will be determined by high performance liquid chromatography. GRH secretion from GRH-containing neuronal cells in culture will be studied and the effects of secretogogues determined. GRH and SRIF action on the pituitary will be studied in the GH deficient lit/lit mouse and membrane fusion will be performed in an attempt to correct the previously reported abnormality presumed to reside in the GRH receptor. Our newly developed somatomammotroph cell line, the first that exhibits GRH sensitivity, will be used to study the effects of GRH and SRIF at cell membrane and nuclear levels. A comparison of exogenous and endogenous (by transfection of the GRH gene) GRH effects will also be compared. The molecular structure of circulating GRH in human plasma will be determined and the mechanism of GH feedback effects in normals and in subjects with disorders of GH secretion will be assessed. The results of these studies will provide a better understanding of the role of the central nervous system in clinical disorders of GH secretion and may ultimately lead to new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK030667-15
Application #
2138481
Study Section
Special Emphasis Panel (NSS)
Project Start
1981-07-02
Project End
1997-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kim, E; Sohn, S; Lee, M et al. (2006) Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes. J Endocrinol 188:263-70
Sandoval, Raudel; Xue, Jiaping; Tian, Xinyong et al. (2006) A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes. Exp Cell Res 312:2465-75
Luque, Raul M; Duran-Prado, Mario; Garcia-Navarro, Socorro et al. (2006) Identification of the somatostatin receptor subtypes (sst) mediating the divergent, stimulatory/inhibitory actions of somatostatin on growth hormone secretion. Endocrinology 147:2902-8
Kamegai, Jun; Tamura, Hideki; Shimizu, Takako et al. (2004) The role of pituitary ghrelin in growth hormone (GH) secretion: GH-releasing hormone-dependent regulation of pituitary ghrelin gene expression and peptide content. Endocrinology 145:3731-8
Luque, R M; Park, S; Peng, X-D et al. (2004) Homologous and heterologous in vitro regulation of pig pituitary somatostatin receptor subtypes, sst1, sst2 and sst5 mRNA. J Mol Endocrinol 32:437-48
Park, Seungjoon; Sohn, Sookjin; Kineman, Rhonda D (2004) Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat. J Endocrinol 180:369-78
Luque, Raul M; Kineman, Rhonda D; Park, Seungjoon et al. (2004) Homologous and heterologous regulation of pituitary receptors for ghrelin and growth hormone-releasing hormone. Endocrinology 145:3182-9
Park, Seungjoon; Kamegai, Jun; Kineman, Rhonda D (2003) Role of glucocorticoids in the regulation of pituitary somatostatin receptor subtype (sst1-sst5) mRNA levels: evidence for direct and somatostatin-mediated effects. Neuroendocrinology 78:163-75
Peng , X D; Park, S; Gadelha, M R et al. (2001) The growth hormone (GH)-axis of GH receptor/binding protein gene-disrupted and metallothionein-human GH-releasing hormone transgenic mice: hypothalamic neuropeptide and pituitary receptor expression in the absence and presence of GH feedback. Endocrinology 142:1117-23
Kineman, R D; Teixeira, L T; Amargo, G V et al. (2001) The effect of GHRH on somatotrope hyperplasia and tumor formation in the presence and absence of GH signaling. Endocrinology 142:3764-73

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