Setting the trajectory

设置轨迹

• 批准号: 8902631
• 负责人: Stacy Schmidt Drury
• 金额: $ 10.19万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902631
• 关键词: Achievement; Address; African American; Age-Months; Attenuated; Behavioral; Biological; Child; Complex; Development; Diagnostic and Statistical Manual of Mental Disorders; Discrimination; Early Intervention; Effectiveness of Interventions; Enrollment; Environment; Epigenetic Process; Exposure to; Face; Funding; Gene Expression; Genetic; Health; Hydrocortisone; Individual; Infant; Intervention; Lead; Length; Life; Life Cycle Stages; Link; Measurement; Measures; Mental disorders; Messenger RNA; Methodology; MicroRNAs; Mission; Molecular; Motion; National Institute of Environmental Health Sciences; National Institute of Mental Health; Outcome; Parents; Pathway interactions; Physiological; Play; Pregnant Women; Preventive Intervention; Procedures; Prospective Studies; Psychopathology; Psychophysiology; Public Health; Research; Risk; Role; Saliva; Salivary; Sampling; Secure; Security; Source; Stress; System; Tacrolimus Binding Proteins; Testing; Therapeutic; Time; Toddler; Transcend; United States National Institutes of Health; Woman; base; biological adaptation to stress; design; disease classification; early childhood; effective intervention; health disparity; hypothalamic pituitary axis; innovation; insight; mRNA Expression; mRNA Precursor; maternal stress; novel; prenatal; public health relevance; racial discrimination; repaired; response; stressor; telomere

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.

描述（由申请人提供）：为了识别高危儿童，需要与早期生活逆境相关的生物变化的精确指标，包括产前母亲压力（PNMS）和种族差异。如果没有能够提供机械洞察力的可靠指标，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 相关。研究还发现，亲子依恋的破坏以及这种关系的治疗修复也会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效用。此外，虽然皮质醇表明 HPA 轴失调，但它提供的机械信息很少。遗传和表观遗传因素（包括 FKBP5 和 miRNA）对 HPA 轴的反应性和适应的既定作用表明它们在潜在机制中发挥着重要作用。同时测量基因表达、miRNA 和皮质醇有望更强有力地定义早期逆境是如何在生物学中嵌入的。唾液是一种理想的可利用生物来源，反映了个体复杂的内部环境。最近的证据表明，可以可靠地测量唾液中的 mRNA、miRNA 和端粒长度。研究还表明，这些标志物随着早期逆境和压力的暴露而发生变化。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，并且是寻求绘制精神疾病和心理疾病轨迹的研究的关键下一步。 定义最早的干预时间点。本研究期望招募具有广泛 PNMS 特征和母亲孕前逆境特征的非裔美国妇女的婴儿。将在已知压力源之前和之后收集唾液，该压力源旨在在两个早期发育时间点激活 HPA 轴。婴儿在依恋发展之前（4 个月，使用静脸程序）和之后（12 个月，使用陌生情境程序 (SSP)）会受到压力。将确定皮质醇对应激源的反应、应激源前/后 FKBP5 mRNA 的倍数变化以及 miR-134 和 miR-16 的初始水平以及端粒长度。利用与倾向评分匹配相关的增加的统计功效，该提案将测试 PNMS、依恋和唾液标记之间的关联，同时控制孕前逆境。该提案目标的实现预计将提供增强的生物学证据，支持在生命历程早期实施基于依恋的干预措施。更有效地解决持续的健康差异并减少与毒性应激相关的负面健康结果的迫切需要需要开发创新方法，既定义生物学机制，又跟踪行为、生理和分子水平干预措施的有效性。