Setting a trajectory: biological markers of early stress and child development

描述（由申请人提供）：为了识别有风险的儿童，需要精确的与早期生活逆境相关的生物学变化指标，包括产前母亲压力（PNMS）和种族差异。如果没有能够提供机制洞察的可靠指标，设计和实施创新干预措施以及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。亲子依恋的中断，以及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，儿童早期的应激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效用。此外，虽然皮质醇表明HPA轴失调，但它提供的机制信息很少。包括FKBP5和mirna在内的遗传因子和表观遗传因子对HPA轴的响应性和适应性的作用表明，它们在HPA轴的潜在机制中发挥了重要作用。同时测量基因表达、miRNA和皮质醇，有望更有力地定义早期逆境是如何生物嵌入的。唾液是一种理想的可接近的生物来源，它反映了个体复杂的内部环境。最近的证据表明，mRNA， miRNA和端粒长度可以可靠地测量唾液。研究还表明，这些标记随着早期逆境和压力的暴露而发生变化。这些共同的发现表明，同时测量每个组成部分的表观遗传心理生理概况是可行的，并且是寻求绘制精神疾病和精神疾病轨迹研究的关键下一步

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.