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)会增加成年后不适应社会情绪、认知和行为功能以及心理和身体健康问题的风险。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。有相当大的公共卫生需要开发有效的工具来识别高危个体，并阐明造成ELS不良影响的机制，以便可以设计适当的预防和治疗策略。最近的数据表明，端粒长度(TL)可能是一种有希望的生物标志物，用于识别ELS诱导的适应不良结果的风险个体。更快速的TL磨损， 作为细胞老化的指标，它既与压力暴露有关，也与糟糕的健康结果有关。到目前为止，TL和健康结果之间的关联几乎只在动物研究中进行了测试，并在成人中进行了回顾性、横断面设计。需要进行纵向的前瞻性研究，以确定TL在预测儿童发展结果方面的效用。此外，相关机制可能是ELS和TL之间以及ELS与不良健康结果之间的联系的原因。识别这些机制可能会导致新的干预策略。这项拟议研究的目的是测试ELS、TL、应激反应(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，前额叶皮质(PFC)功能与一生中一系列社会情感、认知、行为和心理健康结果有关。这项研究的目标将通过遵循已建立的种族/民族混合城市怀孕队列(N=250)、代际压力机制规划(PRISM)项目(R01HL095606)来实现。这项拟议的研究将建立在PRISM的广泛数据库的基础上，该数据库包括从怀孕到两岁的全面、重复的压力暴露、压力反应性和神经行为功能评估，以及重复收集血液、唾液、头发和尿液的广泛生物库。这项新举措将把收集这些措施的范围扩大到5岁，以检查(A)产前应激和出生时TL；(B)ELS和TL损耗到5岁；(C)产前应激反应、氧化应激和出生时TL；(D)应激反应、氧化应激和TL损耗到5岁；(E)出生时TL、TL损耗和PFC功能到5岁。这项研究的创新之处在于：(A)全面评估在产前和婴儿期测量的与端粒生物学有关的应激暴露；(B)测试TL与儿童神经行为功能之间的联系；(C)全面、最先进的应激反应性评估方法；(D)前瞻性纵向设计，它可能增加对暴露、应激反应、细胞衰老和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战略，以防止一生中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.