Cytokine-HPA Interactions During Pregnanacy

怀孕期间细胞因子-HPA 相互作用

• 批准号: 6674816
• 负责人: BRADLEY D PEARCE
• 金额: $ 19.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-24 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6674816
• 关键词: antidepressants; clinical research; cord blood; corticotropin releasing factor; cortisol; cytokine; enzyme linked immunosorbent assay; female; hormone regulation /control mechanism; human subject; hypothalamic pituitary adrenal axis; macrophage; major depression; migration inhibition factor; pregnancy; pregnancy circulation; radioimmunoassay; women' s health

DESCRIPTION (provided by applicant): 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 1A) 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.

描述（由申请人提供）：怀孕是一个剧烈生理变化的时期，包括下丘脑-垂体-肾上腺（HPA）轴张力的改变。在重度抑郁症中，HPA轴的调节异常已被很好地描述，越来越多的证据表明，这些变化可能部分是由糖皮质激素受体（GR）对内源性皮质醇的抵抗引起的，从而损害了大脑中促肾上腺皮质激素释放激素（CRH）的反馈抑制。巨噬细胞迁移抑制因子（MIF）是一种免疫激素分子，可以抑制皮质醇对GR的影响。基于我们的初步发现，正常妊娠时MIF增加了11倍，而在妊娠合并母亲抑郁症时MIF增加了28倍（p<0.0001），我们提出了MIF升高导致糖皮质激素抵抗的假设的初步检验。这导致促炎细胞因子增加（通常由皮质醇抑制）和CRH失调，最终导致抑郁症状的发展。为了探索这一假设，并为进一步在模型系统中验证相关机制提供初步线索，我们提出以下目标：AIM 1A)验证MIF在妊娠过程中升高，并在产前抑郁妇女中进一步升高的假设。目的：确定MIF的升高是否与HPA轴活性的改变和/或血浆促炎细胞因子的增加有关，而血浆促炎细胞因子通常由皮质醇调节。抗抑郁药物对MIF和相关免疫激素介质的影响也将被检查。目的2)确定孕妇妊娠或分娩时MIF升高是否与新生儿循环中MIF或其他免疫激素分子的变化相关。目的3)探讨母体MIF升高与妊娠并发症和/或不良新生儿结局风险增加相关的假设。这些目标的完成有可能为产妇抑郁症的病理生理学提供突破性的见解，并可能揭示产科并发症（如早产）的新的血清学预后指标。此外，本研究为针对抑郁症和产科并发症的治疗开辟了一个新的潜在方向。