Genetic Modulators of HPA-Axis Regulation, Stress Sensitivity

下丘脑-垂体-肾上腺（HPA）轴介导许多应激适应，HPA功能障碍 发生在抑郁症和其他与压力有关的疾病中。妊娠期间，HPA相关机制 通过胎盘介导母体和胎儿间室之间的压力相关通信， 其分泌促肾上腺皮质激素释放激素（CRH）。指导项目2的首要假设是， 胎儿和编码下丘脑-垂体-肾上腺（HPA）轴的关键组成部分， 通过调节（i）敏感性， 胎儿的环境，和（ii）胎儿-母体沟通的胎盘介导。 我们将使用基于家庭的关联方法（FBAT和PBAT）来解决这一假设，通过追求“ 具体目的：（1）研究母体应激和胎儿基因型对胎盘功能的影响， HPA相关基因的表达，（2）探讨胎儿HPA相关基因多态性与胎儿发育的关系。 基因与母胎血清CRH、CRHBP和皮质醇浓度的关系，（3）检测 胎儿HPA轴相关基因的基因型和单倍型与胎儿和新生儿结局（子宫血 流量，出生体重和婴儿皮质醇反应接种后和陌生情况），和（4）测试X基因 环境的相互作用，环境是低与高产妇压力在怀孕期间， 具体目标2和3中审查的成果。 公共卫生相关性：越来越多的证据表明，产妇抑郁症和其他与压力有关的 怀孕期间发生的疾病对胎儿和婴儿的结果产生负面影响。HPA相关机制 似乎是母亲压力和抑郁症之间关系的关键介质和调节剂， 这样的结果。了解特定HPA轴相关基因的变异是否以及如何改变 后代对母亲压力和抑郁的脆弱性可能阐明了基因产物的作用， 编码阴性（和阳性）胎儿和婴儿的结果。这些知识将有助于早期干预 针对高危儿童及其母亲的战略

The hypothalamic-pituitary-adrenal (HPA) axis mediates many adaptations to stress, and HPA dysfunction occurs in depression and other stress-related disorders. During pregnancy, HPA-related mechanisms mediate stress-related communication between the maternal and fetal compartments through the placenta, which secretes corticotrophin-releasing hormone (CRH). The overarching hypothesis guiding Project 2 is that fetal and encoding key components of the hypothalamic-pituitary-adrenal (HPA) axis substantially influence fetal vulnerability to intrauterine exposures and maternal emotional distress by modulating (i) the sensitivity of the fetus to the milieu, and (ii) fetal-maternal communication mediated by the placenta. We will use family-based association methods (FBAT and PBAT) to address that hypothesis, by pursuing' the following Specific Aims: (1) examine the effects of maternal stress and fetal genotypes on placental expression of HPA-related genes, (2) examine the relationship among fetal polymorphisms in HPA-related genes and maternal and fetal serum concentrations of CRH, CRHBP and cortisol, (3) test the association of fetal genotypes and haplotypes of HPA-axis related genes with fetal and neonatal outcome (uterine blood flow, birth weight and infant cortisol response after inoculation and strange situation), and (4) test for gene x environment interactions, the environment being low vs. high maternal stress during pregnancy on the outcomes examined in Specific Aims 2 and 3. Public-health relevance: Increasing evidence suggests that maternal depression and other stress-related disorders occurring during pregnancy negatively impact fetal and infant outcomes. HPA-related mechanisms appear to be critical mediators and modulators of the relationship between maternal stress and depression, and such outcomes. Understanding whether and how variation at specific HPA-axis-related genes alters the vulnerability of offspring to maternal stress and depression may elucidate the role of the gene products they encode in negative (and positive) fetal and infant outcomes. Such knowledge will facilitate early-intervention strategies for at-risk children, and their mothers