Pregnancy is a time of dramatic physiological changes that include alterations in the tone of the hypothalamic pituitary adrenal (HPA) axis. Abnormalities in the regulation of the HPA axis have been well described in major depression, and there is mounting evidence that these changes may be caused in part by resistance of glucocorticoid receptors (GR) to endogenous cortisol, hence impairing feedback inhibition on corticotropin releasing hormone (CRH) in the brain. Macrophage migration inhibitory factor (MIF) is an immunohormonal molecule that overrides the effect of cortisol on the GR. Based on our preliminary findings that MIF is increased 11 fold in normal pregnancy, and is significantly (p<0.0001) more increased (28 fold) in pregnancy complicated by maternal depression, we propose an initial examination of the hypothesis that elevations in MIF cause glucocorticoid resistance, which leads to increased proinflammatory cytokines (normally dampened by cortisol), and dysregulation of CRH, resulting ultimately in the development of depressive symptoms. In order to explore this hypothesis and provide initial clues to relevant mechanisms that can be further tested in model systems, the following aims are proposed:
AIM 1 A) Test the hypothesis that MIF rises over the course of pregnancy, and is further elevated in women with antepartum depression.
AIM 1 B) to determine if elevations in MIF are associated with changes in HPA axis activity and/or increases in plasma proinflamatory cytokines that are normally regulated by cortisol. The effects of antidepressant medications on MIF and related immunohormonal mediators will also be examined.
AIM 2) Determine if elevations in maternal MIF during pregnancy or at delivery correlate with changes in MIF or other immunohormonal molecules in neonatal circulation.
AIM 3) Explore the hypothesis that elevated maternal MIF corresponds with an increased risk for pregnancy complications and/or adverse neonatal outcome. Completion of these Aims holds the potential for ground-breaking insights into the pathophysiology of maternal depression, and may reveal new serological prognostic indicators for obstetric complications such as preterm labor. Moreover, this study opens a new potential direction for therapeutics aimed at depression and obstetric complications.
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