Setting the trajectory

描述(由申请人提供)：为了识别高危儿童，需要准确地指示与早期生活逆境相关的生物变化，包括产前产妇压力(PNMS)和种族差异。没有能够提供机械性洞察的可靠指标，设计和实施创新干预措施并改变消极发展轨迹的能力仍然有限。由唾液皮质醇水平决定的应激反应系统的改变与PNMS有关。中断的亲子依恋，以及这种关系的治疗性修复，也被发现影响婴儿的皮质醇反应。然而，儿童早期的压力低反应期可能会限制皮质醇在这一关键发育时间点作为独立指标的用途。此外，虽然皮质醇提示HPA轴的失调，但它提供的机械性信息最少。遗传和表观遗传因素，包括FKBP5和miRNAs，对HPA轴的响应和适应的既定作用表明，它们在潜在的机制中发挥着重要作用。基因表达、miRNA和皮质醇的同时测量有望更有力地确定早期逆境是如何在生物学上嵌入的。唾液是一种理想的可获得的生物来源，反映了一个人复杂的内部环境。最近的证据表明，在唾液中可以可靠地测量出mRNA、miRNA和端粒长度。研究还表明，随着早期的逆境和压力的暴露，这些标志物中的每一个都会发生变化。这些集体发现表明，同时测量每个组成部分的表观遗传心理生理学特征是可行的，也是寻求绘制精神疾病和 定义最早的干预时间点。这项研究期望招募具有广泛PNMS特征和母亲先入为主的逆境的非裔美国妇女的婴儿。唾液将在已知的应激源之前和之后收集，该应激源旨在激活HPA轴在两个早期发育时间点。婴儿将在(4个月，使用静止面孔程序)和之后(12个月，使用奇异情况程序(SSP))发展依恋。测定皮质醇对应激源的反应，应激源前后FKBP5mRNA的折叠变化，以及miR-134和miR-16的初始水平和端粒长度。利用与倾向分数匹配相关的增加的统计能力，这项建议将测试PNMS、依恋和唾液标记之间的关联，同时控制先入为主的逆境。该提案目标的实现预期将提供更多的生物学证据，支持在生命周期早期实施基于依恋的干预措施。为了更有效地解决持续存在的健康差距并减少与中毒应激相关的负面健康后果，迫切需要开发创新的方法，既定义生物机制，又在行为、生理和分子水平上跟踪干预措施的有效性。

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.