Genetic Modulators of HPA-Axis Regulation, Stress Sensitivity

HPA 轴调节、应激敏感性的遗传调节剂

• 批准号: 8111194
• 负责人: Joseph F. Cubells
• 金额: $ 23.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111194
• 关键词: Address; Adrenal Glands; Birth Weight; Blood flow; Candidate Disease Gene; Child; Communication; Complement; Corticotropin-Releasing Hormone; DNA; Early treatment; Environment; Exposure to; Family; Fetus; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Hormones; Hydrocortisone; Hypothalamic structure; Individual; Infant; Intervention; Knowledge; Maternal Exposure; Mediating; Mediator of activation protein; Mental Depression; Messenger RNA; Methods; Mothers; Neonatal; Outcome; Perinatal Exposure; Phenotype; Physiology; Pituitary Gland; Placenta; Pregnancy; Proteins; Regulation; Risk; Role; Serum; Stress; Testing; Tissues; Variant; Work; base; biological adaptation to stress; emotional distress; fetal; hypothalamic-pituitary-adrenal axis; infant outcome; mRNA Expression; maternal depression; maternal serum; maternal stress; offspring; public health relevance; response; stress related disorder

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

下丘脑-垂体-肾上腺 (HPA) 轴介导许多对压力的适应和 HPA 功能障碍 发生在抑郁症和其他与压力相关的疾病中。妊娠期间，HPA相关机制 通过胎盘介导母体和胎儿室之间与压力相关的沟通， 它分泌促肾上腺皮质激素释放激素（CRH）。指导项目 2 的总体假设是 胎儿和编码下丘脑-垂体-肾上腺 (HPA) 轴关键成分的显着影响 通过调节（i）敏感性来降低胎儿对宫内暴露和母亲情绪困扰的脆弱性 胎儿与周围环境的关系，以及（ii）胎盘介导的胎儿与母体之间的交流。 我们将使用基于家庭的关联方法（FBAT 和 PBAT）来解决该假设，通过追求“ 具体目标如下：（1）考察母体应激和胎儿基因型对胎盘的影响 HPA相关基因的表达，（2）考察HPA相关胎儿多态性之间的关系 基因与母体和胎儿血清 CRH、CRHBP 和皮质醇浓度的关系，(3) 检验 HPA轴相关基因的胎儿基因型和单倍型与胎儿和新生儿结局（子宫血 接种后和奇怪情况下的流量、出生体重和婴儿皮质醇反应），以及（4）基因x测试 环境相互作用，怀孕期间环境较低与母亲压力较高 具体目标 2 和 3 中审查的结果。 公共卫生相关性：越来越多的证据表明，孕产妇抑郁症和其他与压力有关的疾病 怀孕期间发生的疾病会对胎儿和婴儿的结局产生负面影响。 HPA相关机制 似乎是母亲压力和抑郁之间关系的关键调解者和调节者， 以及这样的结果。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会阐明其基因产物的作用 编码阴性（和阳性）胎儿和婴儿结果。这些知识将有助于早期干预 针对高危儿童及其母亲的策略