Hormones from the hypothalamus mediate interactions between the nervous and endocrine systems by controlling the activity of specific target cells in the anterior pituitary gland. The hypothalamic peptide growth hormone-releasing hormone (GHRH) acts on pituitary somatotroph cells to stimulate their proliferation during development and to regulate their ability to produce and secrete growth hormone (GH).
Specific Aim 1 of this proposal will investigate the transcriptional regulatory factors and external hormonal influences involved in somatotroph differentiation, using the GHRH receptor as an important marker of the somatotroph cell lineage.
Aim 1 A will examine somatotroph cell-specific expression of the GHRH receptor gene, using cell transfection and transgenic animal approaches to identify important gene regulatory elements and transcriptional regulatory factors.
Aim 1 B will extend these studies by establishing how steroid hormones modulate expression of the GHRH receptor gene during development, leading to alterations in pituitary responsiveness to GHRH and to sexually dimorphic patterns of GH secretion.
Specific Aim 2 of this proposal will investigate the signal transduction pathways leading to somatotroph cell proliferation and GH synthesis and secretion, using signaling through the GHRH receptor as a model.
Aim 2 A will examine GHRH-stimulated MAP kinase activation and cell proliferation in a GHRH-responsive pituitary somatotroph cell line.
Aim 2 B will extend these studies by defining interactions between the signaling pathways activated by GHRH and those activated by synthetic GH secretagogues, leading to the synergistic actions of these hormonal factors on pituitary GH secretion. The investigator expects that these studies of the regulation and activity of the GHRH receptor will provide insights into pituitary somatotroph cell function and thus an understanding of diseases of the GH axis that are relevant to human health.
|McElvaine, Allison T; Mayo, Kelly E (2006) A dominant-negative human growth hormone-releasing hormone (GHRH) receptor splice variant inhibits GHRH binding. Endocrinology 147:1884-94|
|Cunha, Shane R; Mayo, Kelly E (2002) Ghrelin and growth hormone (GH) secretagogues potentiate GH-releasing hormone (GHRH)-induced cyclic adenosine 3',5'-monophosphate production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology 143:4570-82|
|Voss, T C; Goldman, L R; Seek, S L et al. (2001) GH mRNA levels are elevated by forskolin but not GH releasing hormone in GHRH receptor-expressing MtT/S somatotroph cell line. Mol Cell Endocrinol 172:125-34|
|Lee, E J; Kotlar, T J; Ciric, I et al. (2001) Absence of constitutively activating mutations in the GHRH receptor in GH-producing pituitary tumors. J Clin Endocrinol Metab 86:3989-95|
|Mayo, K E; Miller, T; DeAlmeida, V et al. (2000) Regulation of the pituitary somatotroph cell by GHRH and its receptor. Recent Prog Horm Res 55:237-66; discussion 266-7|
|Miller, T L; Godfrey, P A; Dealmeida, V I et al. (1999) The rat growth hormone-releasing hormone receptor gene: structure, regulation, and generation of receptor isoforms with different signaling properties. Endocrinology 140:4152-65|
|Gaylinn, B D; Dealmeida, V I; Lyons Jr, C E et al. (1999) The mutant growth hormone-releasing hormone (GHRH) receptor of the little mouse does not bind GHRH. Endocrinology 140:5066-74|
|DeAlmeida, V I; Mayo, K E (1998) Identification of binding domains of the growth hormone-releasing hormone receptor by analysis of mutant and chimeric receptor proteins. Mol Endocrinol 12:750-65|
|Miller, T L; Mayo, K E (1997) Glucocorticoids regulate pituitary growth hormone-releasing hormone receptor messenger ribonucleic acid expression. Endocrinology 138:2458-65|