Telomeres as an Epigenetic Marker of Neurodevelopment and Early Adversity

描述（由申请人提供）：早期逆境和负面健康结果之间的关联已经建立，但机制定义不清。端粒长度代表了暴露于逆境的一种有前途的新的表观遗传生物标志物，其暗示细胞衰老是连接早期逆境和负面健康结果的机械生物学途径。早期逆境的客观标记将在早期逆境研究中开辟新的研究途径，目前大多数逆境的测量都是主观的，容易受到偏见的影响。长期目标是更好地了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。这个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，定义影响端粒长度的发育敏感期，并为细胞衰老的破坏是早期逆境“皮下”的一种机制的新假设提供支持。“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，这些逆境已经被仔细描述。在这个已经广泛的数据集上增加前瞻性表观遗传措施，预计将显著增加这项研究的早期逆境和与行为，社会发展，情感发展和神经生物学相关的发展敏感时期的跨领域影响。核心假设是，暴露于早期逆境，特别是在生命的最初几年，改变了端粒磨损的速度。我们进一步期望端粒长度，一个已知的细胞衰老的标志，反映了一个既定的衡量神经发育，特别是脑电图功率。这一假设是根据我们的初步数据和文献综述提出的。这项研究的基本原理是，端粒长度代表了一种可获得的表观遗传生物标志物，并将通过定义一种客观的暴露措施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）确定特定时间点的机构化历史在多大程度上预测端粒长度。2)在一项前瞻性对照研究设计中，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之间的关系。这种方法是创新的，因为它研究了一个独特的，广泛特征的儿童群体的新机制。这项拟议中的研究意义重大，因为它有望通过提供一种可用于跨物种和跨研究的新型表观遗传生物标志物来推进早期逆境的研究。最终，这些知识有可能确定关键的发展时期，并减少早期逆境的跨领域负面健康影响。 公共卫生相关性：这项研究与公共卫生有关，因为端粒长度，早期逆境和儿童神经发育之间的关联将促进对早期逆境影响整个生命周期健康结果的机制的理解。拟议的研究与NIH的部分使命有关，该使命涉及定义将早期不利环境与负面健康结果联系起来的生物机制，定义发展中的敏感时期，并确定性别差异是对逆境的反应。研究结果将提供必要的基础知识，以减少与早期生活逆境相关的负担。

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. PUBLIC HEALTH RELEVANCE: The propose research is relevant to public health because the demonstration of an association between telomere length, early adversity, and neurodevelopment in childhood will advance the understanding of the mechanism by which early adversity influences health outcomes across the lifespan. The proposed research is relevant to part of the NIH's mission that pertains defining the biological mechanism linking early adverse environments to negative health outcomes, defining sensitive periods in development, and identifying gender differences is response to adversity. The results will provide fundamental knowledge necessary to decrease the burdens associated with early life adversity.