CORTICOTROPIN-RELEASING HORMONE PHYSIOLOGY

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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.