Telomeres as an Epigenetic Marker of Neurodevelopment and Early Adversity

描述（由申请人提供）：早期逆境与负面健康结果之间的关联已经建立，但其机制尚不明确。端粒长度代表了逆境暴露的一种有希望的新型表观遗传生物标志物，它暗示细胞衰老是一种连接早期逆境和负面健康结果的机制生物学途径。早期逆境的客观标记将为早期逆境研究开辟新的研究途径，目前大多数逆境测量都是主观的，容易受到偏见的影响。长期目标是更好地理解早期逆境改变正常发育轨迹的机制，并确定暴露改变神经发育轨迹的敏感时期。这一特殊应用的目的是验证端粒长度作为早期逆境的表观遗传生物标志物，确定影响端粒长度的发育敏感时期，并为细胞衰老中断是早期逆境“在皮肤下”的一种机制这一新假设提供支持。布加勒斯特早期干预项目（BEIP）是一项独特的纵向研究，研究对象是暴露于一系列早期逆境的儿童，这些逆境已被仔细描述。在这个已经很广泛的数据集上增加前瞻性的表观遗传学测量，预计将大大增加与行为、社会发展、情感发展和神经生物学相关的早期逆境和发育敏感期的跨领域影响的研究。核心假设是，早期的逆境，特别是在生命的最初几年，会改变端粒磨损的速度。我们进一步期望端粒长度，一个已知的细胞老化的标志，反映了神经发育的既定措施，特别是脑电图功率。这一假设是基于我们的初步数据和文献综述而制定的。提出研究的基本原理是端粒长度代表了一种可接近的表观遗传生物标志物，并将通过定义暴露的客观测量来推进早期逆境的研究。在强有力的初步数据的指导下，我们将通过追求三个具体目标来检验这一假设：1)确定特定时间点的制度化历史对端粒长度的预测程度。2)在对照前瞻性研究设计中，确定端粒长度变化与持续逆境之间的相关性。3)探讨端粒长度与脑电功率的关系。这种方法是创新的，因为它在一个独特的，具有广泛特征的儿童群体中检查了一种新机制。这项研究具有重要意义，因为它有望通过提供一种新的表观遗传生物标志物来推进对早期逆境的研究，这种生物标志物可以跨物种和跨研究使用。最终，这些知识有可能确定关键的发育时期，减少早期逆境对健康的跨领域负面影响。

DESCRIPTION (provided by applicant): The association between early adversity and negative health outcomes has been established, but the mechanism is poorly defined. Telomere length represents a promising novel epigenetic biomarker of exposure to adversity that implicates cellular aging as a mechanistic biological pathway linking early adversity and negative health outcomes. An objective marker of early adversity would open new research pathways in early adversity research where most current measures of adversity are subjective and vulnerable to bias. The long term goal is to better understand the mechanism by which early adversity alters normal developmental trajectories and to define sensitive periods when exposure alters neurodevelopmental trajectories. The objective of this particular application is to validate telomere length as an epigenetic biomarker of early adversity, define sensitive periods in development that impact telomere length, and provide support for the novel hypothesis that a disruption in cellular aging is one mechanism by which early adversity gets "under the skin." The Bucharest Early Intervention Project (BEIP) is a unique longitudinal study of children exposed to a range of early adversity that has been carefully characterized. The addition of prospective epigenetic measures to this already extensive dataset is expected to add significantly to this study of the cross-domain impact of early adversity and sensitive periods in development related to behavior, social development, emotional development and neurobiology. The central hypothesis is that exposure to early adversity, particularly in the first years of life, alters the rate of telomere attrition. We further expect that telomere length, a known marker of cellular aging, reflects an established measure of neurodevelopment, specifically EEG power. This hypothesis has been formulated on the basis of our preliminary data and review of the literature. The rationale for the proposed research is that telomere length represents an accessible epigenetic biomarker and will advance the study of early adversity by defining an objective measure of exposure. Guided by strong preliminary data, we will test the hypothesis by pursuing three specific aims: 1) To determine the degree to which institutionalization history at specific time points predicts telomere length. 2) To determine the correlation, in a controlled prospective study design, between change in telomere length and ongoing adversity. 3) To examine the association between telomere length and EEG power. This approach is innovative because it examines a novel mechanism in a unique, extensively characterized population of children. The proposed research is significant because it is expected to advance the study of early adversity by providing a novel epigenetic biomarker that can be used across species and across studies. Ultimately, this knowledge has the potential to identify critical developmental periods and reduce the cross-domain negative health effects of early adversity.