Corticotropin-releasing factor (CRF) is recognized as the principal regulator of the activity of the hypothalamic-pituitary-adrenal (HPA) axis under both basal and stressful circumstances. In doing so, CRF acts in concert with established secretagogues such as vasopressin, catecholamines and corticosteroids. Recent evidence is accumulating that additionally, a number of other factors [such as melanocyte-concentrating hormone (MCH), activin and interleukin-1(Il-1)] may play a role in modulating the HPA axis. At present, the mechanisms through which stimulation of the HPA axis regulates CRF expression, and the specific role of some of these newly described factors in modulating the HPA axis' response to stimuli, are far from being entirely understood. The purpose of this proposal is, first, to investigate the effect of stress on CRF expression in the brain, using Northern blot analysis and in situ hybridization techniques. In particular, we will examine the possibility that CRF expression is regulated differentially according to the type and/or regimen of administration of the stress, and the age of the animal exposed to the stress. Second, we will explore the pharmacological effects and putative physiological role of newly described factors (MCH, activin and Il-1) reported to alter ACTH secretion, and investigate their interaction with CRF, vasopressin and/or catecholamines in mediated stress-induced ACTH, corticosterone and Beta-endorphin secretion. Third, we will explore some of the mechanisms (including the role of endogenous CRF and Il-1) through which immune activation or inflammation, two powerful stimuli of ACTH secretion, modify the activity of the corticotrophs. Finally, this proposal will evaluate the in vivo activity of selected CRF and GRF analogs, which represent indispensable tools for the studies described above.
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