The overall objective of this research project is to define further the normal and abnormal physiology of corticotropin-releasing hormone (CRH). The efficacy of CRH stimulation during bilateral inferior petrosal vein sampling for plasma immunoreactive (IR) ACTH as a diagnostic test for differentiating Cushing's disease from ectopic ACTH syndrome and/or lateralizing pituitary microadenomas causing Cushing's disease will be evaluated. The intraoperative use of a fluorescent analog of human CRH (hCRH) to identify ACTH-secreting microadenomas either after they have been removed or in situ will be explored in vitro with excised human pituitary tumor tissue and in vivo in animals prior to possible clinical trials. A high molecular weight """"""""IR-hCRH"""""""" in plasma, which may be an aggregate, a precursor, an hCRH- degrading enzyme or a specific carrier protein, will be characterized, and its effect on CRH bioactivity will be determined. The possible proliferative effects of chronic exposure to CRH on pituitary corticotrophs will be investigated in vivo in an animal model in which ovine CRH is infused intracerebroventricularly, and in vitro in dispersed rat anterior pituitary cell cultures. The fine temporal features of regulation of ACTH secretion by CRH and other agonists and antagonists of ACTH secretion and the interactions between the intracellular signal transduction pathways that mediate the actions of CRH, arginine vasopressin and other modulators of ACTH secretion will be elucidated in a dispersed cell microperifusion column system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033334-05
Application #
3231744
Study Section
Endocrinology Study Section (END)
Project Start
1983-12-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
Orth, D N; Shelton, R C; Nicholson, W E et al. (2001) Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression. Arch Gen Psychiatry 58:77-83
Dickstein, G; DeBold, C R; Gaitan, D et al. (1996) Plasma corticotropin and cortisol responses to ovine corticotropin-releasing hormone (CRH), arginine vasopressin (AVP), CRH plus AVP, and CRH plus metyrapone in patients with Cushing's disease. J Clin Endocrinol Metab 81:2934-41
Orth, D N (1995) Cushing's syndrome. N Engl J Med 332:791-803
Won, J G; Orth, D N (1994) Role of lipoxygenase metabolites of arachidonic acid in the regulation of adrenocorticotropin secretion by perifused rat anterior pituitary cells. Endocrinology 135:1496-503
Won, J G; Nicholson, W E; Ching, K N et al. (1993) Effect of protein kinase-C depletion on inositol trisphosphate-mediated and cyclic adenosine 3',5'-monophosphate-dependent protein kinase-mediated adrenocorticotropin secretion. Endocrinology 133:1274-83
Horiba, N; Nicholson, W E; Ch'ng, J L et al. (1993) Chromogranin A does not mediate glucocorticoid inhibition of adrenocorticotropin secretion. Endocrinology 132:1585-92
Gaitan, D; Loosen, P T; Orth, D N (1993) Two patients with Cushing's disease in a kindred with multiple endocrine neoplasia type I. J Clin Endocrinol Metab 76:1580-2
Orth, D N (1992) Corticotropin-releasing hormone in humans. Endocr Rev 13:164-91
Peterson, M E; Kemppainen, R J; Orth, D N (1992) Effects of synthetic ovine corticotropin-releasing hormone on plasma concentrations of immunoreactive adrenocorticotropin, alpha-melanocyte-stimulating hormone, and cortisol in dogs with naturally acquired adrenocortical insufficiency. Am J Vet Res 53:421-5
Oki, Y; Peatman, T W; Qu, Z C et al. (1991) Effects of intracellular Ca2+ depletion and glucocorticoid on stimulated adrenocorticotropin release by rat anterior pituitary cells in a microperifusion system. Endocrinology 128:1589-96

Showing the most recent 10 out of 19 publications