Early life stress, telomere attrition, and child prefrontal cortex functioning

 描述（由申请人提供）：早期生活压力（ELS）增加了适应不良的社会情绪，认知和行为功能以及成年后的身心健康问题的风险。缺乏确定最易受不良后果影响的儿童和实施有效预防战略的方法。有一个相当大的公共卫生需要开发有效的工具，以确定风险的个人，并阐明机制负责不良ELS的影响，使适当的预防和治疗策略可能会设计。最近的数据表明，端粒长度（TL）可能是一个有前途的生物标志物，用于识别ELS诱导的适应不良结局的风险个体。TL损耗更快， 作为细胞老化的指标，它与压力暴露和健康状况不佳有关。迄今为止，TL和健康结果之间的关联几乎完全在动物研究和成年人中进行了回顾性横断面设计。需要进行纵向、前瞻性研究来确定TL在预测儿童期发育结果中的效用。此外，相关的机制可能负责ELS和TL之间的联系，ELS和不良健康结果之间的联系。识别这些机制可能会导致新的干预策略。拟议研究的目标是测试ELS、TL、应激反应性（下丘脑-垂体-肾上腺轴和自主神经系统功能）、氧化应激和前额叶皮质（PFC）功能的重复测量之间的关联，这些功能涉及一生中的一系列社会情感、认知、行为和心理健康结果。研究目的将通过遵循一个已建立的种族/民族混合城市妊娠队列（N=250），即代际压力机制规划（PRISM）项目（R 01 HL 095606）来实现。这项拟议的研究将建立在PRISM广泛的数据库基础上，该数据库包括对从怀孕到两岁的压力暴露、压力反应和神经行为功能的全面、重复评估，以及对血液、唾液、毛发和尿液重复收集的广泛生物储存库。这项新的倡议将这些措施的收集延伸到5岁，以检查（a）产前应激和出生时的TL;（B）5岁时的ELS和TL损耗;（c）产前应激反应性、氧化应激和出生时的TL;（d）5岁时的应激反应性、氧化应激和TL损耗之间的联系;（e）出生时的TL、TL自然减员和5岁之前的PFC功能。本研究的创新之处在于：（a）全面评估了产前和婴儿期至学龄前阶段与端粒生物学相关的压力暴露;（B）测试了TL与儿童期神经行为功能之间的联系;（c）评估压力反应性的全面、最先进的方法;（d）前瞻性纵向设计，这可能会增加对暴露、应激反应、细胞老化和PFC功能之间影响方向的理解。这些发现可以转化为识别和治疗高危儿童的策略，以防止整个生命周期中出现一系列适应不良的结果。

 DESCRIPTION (provided by applicant): Early life stress (ELS) increases risk for maladaptive socioemotional, cognitive, and behavioral functioning and mental and physical health problems through adulthood. Methods for identifying children most vulnerable to poor outcomes and for applying effective prevention strategies are lacking. There is a considerable public health need to develop efficient tools for identifying at-risk individuals and to elucidate mechanisms responsible for adverse ELS effects so that appropriate prevention and treatment strategies may be designed. Recent data suggest that telomere length (TL) may be a promising biomarker for identifying individuals at risk for ELS- induced maladaptive outcomes. More rapid TL attrition, an indicator of cellular aging, has been linked to both stress exposures and to poor health outcomes. To date, associations between TL and health outcomes have been tested almost exclusively in animal studies and among adult humans in retrospective, cross-sectional designs. Longitudinal, prospective research is needed to determine the utility of TL in predicting developmental outcomes in childhood. Moreover, related mechanisms may be responsible for links between ELS and TL and between ELS and poor health outcomes. Identifying these mechanisms may lead to novel intervention strategies. The goal of the proposed study is to test associations among repeated measures of ELS, TL, stress reactivity (hypothalamic-pituitary-adrenal axis and autonomic nervous system functioning), oxidative stress, and prefrontal cortex (PFC) functioning, which is involved in a range of socioemotional, cognitive, behavioral, and mental health outcomes throughout life. The study aims will be accomplished by following an established racially/ethnically-mixed urban pregnancy cohort (N=250), the Programming of Intergenerational Stress Mechanisms (PRISM) project (R01HL095606). The proposed study will build on PRISM's extensive database, which includes comprehensive, repeated assessments of stress exposures, stress reactivity, and neurobehavioral functioning from pregnancy through two years of age and an extensive biorepository of repeated collections of blood, saliva, hair, and urine. This new initiative will extend collection of these measures through age 5 years to examine links among (a) prenatal stress and TL at birth; (b) ELS and TL attrition through age 5 years; (c) prenatal stress reactivity, oxidative stress, and TL at birth; (d) stress reactivity, oxidative stress, and TL attrition through age 5 years; (e) TL at birth, TL attrition, and PFC functioning through age 5 years. This study is novel in its (a) comprehensive assessment of stress exposures measured prenatally and in infancy through the preschool period in relation to telomere biology; (b) testing of links between TL and neurobehavioral functioning in childhood; (c) comprehensive, state-of-the-art methods for assessing stress reactivity; (d) prospective longitudinal design, which may increase understanding of direction of effects among exposures, stress reactivity, and cellular aging and PFC functioning. The findings may be translated into strategies to identify and treat at-risk children to prevent a range of maladaptive outcomes across the lifespan.