Peri-Partum Depression and Genetics of Glucocorticoid Receptor Regulating Genes

描述(由申请人提供)：妊娠期和产后期的严重抑郁是妇女的主要健康问题。以往的研究表明，孕期抑郁是早产和低出生体重的危险因素，对儿童发育产生负面影响，并改变儿童的神经内分泌反应和神经递质水平。最近完成的一项关于怀孕期间母亲抑郁预测因素的合作调查显示，停止服用抗抑郁药物的妇女复发率为68%，选择继续服用抗抑郁药物的妇女复发率为28%。尽管妊娠期抑郁症对公共健康具有明显的重要性，而且一些女性可能在遗传上容易患上抑郁症，但评估影响妊娠期抑郁症易感性的遗传因素的研究很少。这项提案将开始解决妇女健康研究这一未得到充分研究的领域，与两个方案公告中的主题相一致：妇女孕期和产后的心理健康(PA-03-135)和妇女的心理健康和研究中的性别/性别差异(PA-03-143)。目前的提案将研究对神经激素变化的遗传影响，这些变化是孕妇怀孕期间抑郁风险的潜在调节因素，并计划作为对PA-03-135的响应的探索性/发育赠款(R21)。目前提出的最重要的假设是，糖皮质激素和黄体酮在妊娠期间改变了糖皮质激素受体(GR)调节辅助伴侣FKBP5和其他GR相关调节分子的表达，导致了这一时期的适应性GR抵抗。由于GR调节蛋白编码基因的序列变异而导致的GR调节功能障碍，可能会使一些妇女在关键的大脑区域容易受到GR介导的有害影响，从而使她们在产前和产后出现抑郁症状。与公共卫生的相关性：扩大关于可能导致孕期产妇抑郁的遗传机制的知识库，将有助于及早识别处于危险中的妇女。这种对处于危险中的妇女的“先验”识别将直接有助于治疗规划和加强围产期健康、产科结局和婴儿健康。

DESCRIPTION (provided by applicant): Major depression during pregnancy and the postpartum period is a major women's health concern. Previous investigations have demonstrated that maternal depression during pregnancy is a risk factor for pre-term birth and low birth weight, negative effects on child development and altered neuroendocrine responses and neurotransmitter levels in children. A recently completed collaborative investigation of predictors of maternal depression during pregnancy, demonstrated a 68% relapse rate for those discontinuing antidepressants and remarkably a 28% relapse rate in women who choose to continue antidepressants. Despite the clear public- health importance of depression during pregnancy, and the likelihood that some women may be genetically vulnerable to develop depression independent of treatment choices, the research assessing genetic factors influencing vulnerability for depression during pregnancy are sparse. This proposal will begin to address this understudied area of women's health research consistent with themes in two program announcements: Women's Mental Health in Pregnancy and Postpartum (PA-03-135) and Women's Mental Health and Sex/Gender Differences in Research (PA-03-143). The current proposal will examine the genetic influences on neurohormonal alterations that are potential modulators of maternal risk for depression during pregnancy and is planned as an Exploratory/Developmental grant (R21) in response to PA-03-135. The overarching hypothesis guiding the current proposal is that glucocorticoids and progesterone alter the expression of the glucocorticoid receptor (GR)-regulating co-chaperone FKBP5 and other GR-associated regulatory molecules, during pregnancy, leading to adaptive GR resistance during this period. Dysfunction of GR regulation due to sequence variation in genes encoding such regulatory proteins may leave some women vulnerable to GR-mediated deleterious effects in key brain regions, thus predisposing them to depressive symptoms during the ante- and postpartum periods. Relevance to public health: Expanding the knowledge base on the genetic mechanisms potentially contributing to maternal depression during pregnancy will facilitate early identification of women at risk. Such 'a priori' identification of women at risk will directly contribute to treatment planning and enhancement of perinatal health, obstetrical outcome, and infant well-being.