Setting the trajectory

描述（由申请人提供）：为了确定风险儿童与早期生活逆境相关的生物学变化的精确指标，包括产前母亲压力（PNMS）和种族差异是必要的。如果没有可靠的指标能够提供机械的洞察力，设计和实施创新的干预措施，改变消极的发展轨迹的能力仍然有限。应激反应系统的改变，由唾液皮质醇水平决定，与PNMS有关。亲子依恋的中断，以及对这种关系的治疗性修复，也被发现会影响婴儿的皮质醇反应。然而，在幼儿期的压力低反应期可能会限制皮质醇作为一个独立的指标在这个关键的发展时间点的效用。此外，虽然皮质醇表明HPA轴的失调，但它提供的机制信息很少。遗传和表观遗传因子（包括FKBP 5和miRNA）对HPA轴的反应性和适应性的既定作用表明它们在潜在机制中发挥重要作用。同时测量基因表达、miRNA和皮质醇有望更有力地确定早期逆境是如何生物嵌入的。唾液是一种理想的生物来源，反映了一个人复杂的内部环境。最近的证据表明，mRNA，miRNA和端粒长度可以在唾液中可靠地测量。研究还表明，这些标志物中的每一个都随着早期逆境和压力的暴露而发生变化。这些集体研究结果表明，同时测量每个组成部分的表观遗传心理生理特征是可行的，并且是寻求绘制精神疾病轨迹的研究的关键下一步， 确定最早的干预时间点。本研究期望招募具有广泛PNMS特征和母亲孕前逆境的非裔美国妇女的婴儿。在两个早期发育时间点，收集已知应激源前后的唾液，该应激源旨在激活HPA轴。婴儿将在依恋发展之前（4个月，使用静止面部程序）和之后（12个月，使用陌生情境程序（SSP））受到压力。将测定皮质醇对应激物的反应、应激物前/后FKBP 5 mRNA的倍数变化以及miR-134和miR-16的初始水平和端粒长度。利用与倾向评分匹配相关的增加的统计功效，该提议将测试PNMS、依恋和唾液标志物之间的关联，同时控制孕前逆境。本提案目标的实现预计将提供增强的生物学证据，以支持在生命早期实施基于依恋的干预措施。迫切需要更有效地解决持续的健康差距和减少与毒性应激相关的负面健康结果，这需要开发创新的方法，既定义生物机制，又跟踪行为，生理和分子水平上干预措施的有效性。

DESCRIPTION (provided by applicant): To identify at-risk children precise indicators of the biological changes associated with early life adversity, including prenatal maternal stress (PNMS) and racial disparities are needed. Without reliable indicators capable of providing mechanistic insight the ability to design and implement innovative interventions, and alter negative developmental trajectories, remains limited. Alterations in the stress response system, determined by salivary cortisol levels, are associated with PNMS. Disrupted parent-child attachment, as well as the therapeutic repair of this relationship, has also been found to influence the cortisol response in infants. However, the stress hypo-responsive period in early childhood may limit the utility of cortisol as a stand-alone indicator during this critical developmental time point. Additionally, while cortisol indicates dysregulation in the HPA axis it provides minimal mechanistic information. The established role of genetic and epigenetic factors, including FKBP5 and miRNAs, to both the responsiveness and adaptation of the HPA axis suggest they play an important role in the underlying mechanism. Concurrent measurement of gene expression, miRNA, and cortisol is expected to more robustly define how early adversity is biological embedded. Saliva represents an ideal accessible biological source that reflects an individual's complex internal milieu. Recent evidence indicates that mRNA, miRNA and telomere length can be reliably measured in saliva. Studies have also demonstrated changes in each of these markers with exposure to early adversity and stress. These collective findings indicate that an epigenetic psychophysiological profile concurrently measuring each component is feasible and a critical next step in research seeking to chart the trajectory of mental illness and define the earliest intervention time points. This study expects to enroll infants of African American women with extensive characterization of PNMS and maternal preconception adversity. Saliva will be collected pre and post a known stressor designed to activate the HPA axis at two early developmental time points. Infants will be stressed before (4 months, using the Still Face Procedure) and after (12 months, using the Strange Situation Procedure (SSP)) the development of attachment. The cortisol response to the stressor, fold change in FKBP5 mRNA pre/post the stressor as well as initial levels of miR-134 and miR-16 and telomere length will be determined. Leveraging the increased statistical power associated with propensity score matching this proposal will test the association between PNMS, attachment and salivary markers while controlling for preconception adversity. Achievement of the proposal aims of this proposal is expected to provide enhanced biological evidence in support of the implementation of attachment based interventions early in the life course. The critical need to more effectively address persistent health disparities and decrease the negative health outcomes associated with toxic stress requires the development of innovative methodologies that both define biological mechanisms and track the effectiveness of interventions at the behavioral, physiologic, and molecular level.