Evaluation of the peripheral CLOCK system in Cushings Disease

Abstract

Glucocorticoids regulate a large number of functions as metabolic control, the cardiovascular, immune and nervous system, besides influencing and modulating behavior. The unbalance of the Hypothalamus-pituitary-adrenal (HPA) axis, with the consequent chronic exposure to elevated levels of glucocorticoids, as happens in Cushing's Disease (ACTH secretory pituitary tumor), leads to several systemic clinical manifestations, such as central obesity, skin abnormalities, cardiovascular abnormalities as hypertension, neuropsychiatric, reproductive, metabolic and endocrine disfunctions as insulin resistance and dyslipidemia, characterizing the Cushing's Syndrome. The circadian rhythm of the HPA axis depends on the action of a molecular temporizing system (the CLOCK system) expressed in the suprachiasmatic nucleus (SCNs) of the hypothalamus and in peripheral oscillators, allowing circulating levels of glucocorticoids to be regulated and naturally fluctuate along 24 hours. Reciprocally, the HPA axis influences the CLOCK system activity, because glucocorticoids affect the peripheral oscillators in nearly every organ and tissue. In the present study, the genic expression of the clock system (CLOCK, BMAL1, PER1, PER2, PER3, CRY1 E CRY2 genes) will be evaluated by real time PCR (TaqMan®) in individuals with Cushing's Syndrome (n = 12) and in healthy individuals (n = 12). The analysis of the gene expression of the CLOCK system will be performed in peripheral blood. Differences among groups will be analysed by non-parametric methods (Friedman's test). The significance level adopted will be p<0,05. (AU)