Environment, Imprinting, and Neurodevelopment

环境、印记和神经发育

• 批准号: 8838798
• 负责人: Jia Chen
• 金额: $ 77.21万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838798
• 关键词: Arousal; Autistic Disorder; Behavior Disorders; Biological Markers; Bipolar Disorder; Birth; Brain; Child; Child health care; Clinical; Cohort Studies; Complex; DNA Methylation; Data; Data Collection; Defect; Development; Diagnostic; Disease; Early Intervention; Early identification; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Exposure to; Fetal Development; Fetus; Future; Gene Expression; Genes; Genomic Imprinting; Gilles de la Tourette syndrome; Goals; Growth and Development function; Health; Impaired cognition; Infant; Intervention; Laboratories; Life Style; Link; Measures; Mediating; Mental Health; Mental disorders; Metal exposure; Methylation; Modeling; Movement; Neurodevelopmental Deficit; Neurologic; Neurotoxins; New Hampshire; Newborn Infant; Organ; Outcome; Pathway interactions; Pattern; Perinatal Exposure; Placenta; Play; Prevention; Procedures; Psyche structure; Public Health; Research; Resources; Rhode Island; Risk; Role; Schizophrenia; Shapes; Socioeconomic Status; Staging; Tissues; Trace metal; Work; Xenobiotics; alertness; base; behavioral health; biobank; cohort; epigenetic marker; experience; fetal programming; imprint; improved; in utero; mRNA Expression; molecular marker; neurobehavior; neurobehavioral; neurodevelopment; neuromuscular function; novel; novel strategies; psychological distress; psychosocial; sample collection; socioeconomics; tool

DESCRIPTION (provided by applicant): There is growing evidence that lifelong health, including mental health, is particularly shaped by the environment experienced during the in-utero developmental period. The intrauterine environment is influenced by a complex variety of factors, including maternal lifestyle, environmental exposures, socioeconomic status, and psychosocial aspects, making risk determination based on identification of these factors difficult and inaccurate. Yet, defining children at-risk early is utterly critical to improving future mental health outcomes. Due to the unique regulatory features of imprinted genes and their sensitivity to environmental exposures, genomic imprinting has been proposed as an ideal integrated measure of the intrauterine environment for use in epidemiologic studies of the developmental origins of health and disease. As imprinted genes in the placenta can impact the function of this critical organ in directing fetal development and programming, there is also strong evidence to support establishing and validating the link between alterations in imprinting and newborn neurodevelopmental outcomes. Compelled by strong rationale and by emerging evidence, including work from our laboratories linking placenta imprinted gene expression to infant neurodevelopment, this project aims to develop an imprinting-based biomarker that can prospectively predict neurobehavioral outcomes, which ultimately can be used for immediate identification of infants at-risk in order for early intervention to be initiated/implemented. We have developed a multi-stage research plan to first utilize the comprehensive resources of the ongoing Rhode Island Child Health Study (RICHS), which employs the validated and prospectively predictive NICU Network Neurobehavioral Scales (NNNS) as a phenotypic measure of newborn neurobehavior in a birth cohort of 900 newborn infants, to define a biomarker panel associated with key neurobehavioral measures. We will then demonstrate the validity and generalizability of this biomarker using an established but independent resource, the New Hampshire Birth Cohort Study (NHBCS), which uses similar data collection procedures as RICHS. In addition, although the environment is extraordinarily complex, we have decided to focus on fetal exposure to metals, specifically those which are widely considered neurotoxins or those considered protective, as a paradigm to build a comprehensive model to examine the inter-relationships among in utero trace metals exposure, genomic imprinting, and newborn neurobehavioral outcomes. Identification of an imprinting signature associated with abnormal neurodevelopment or environmental exposure would have significant clinical and public health implications by pinpointing certain environmental risk factors for neurobehavioral defects or serve as a basis for early diagnostic tools thus providing an opportunity for early intervention.

描述（由申请人提供）：越来越多的证据表明，终身健康，包括心理健康，尤其受到子宫内发育期间经历的环境的影响。宫内环境受到多种复杂因素的影响，包括母亲的生活方式、环境暴露、社会经济状况和社会心理方面，使得基于识别这些因素的风险确定变得困难且不准确。然而，尽早确定处于危险中的儿童对于改善未来的心理至关重要 健康结果。由于印记基因的独特调控特征及其对环境暴露的敏感性，基因组印记已被提议作为子宫内环境的理想综合测量方法，用于健康和疾病发育起源的流行病学研究。由于胎盘中的印记基因可以影响这一关键器官在指导胎儿发育和编程方面的功能，因此也有强有力的证据支持建立和验证印记改变与新生儿神经发育结果之间的联系。在强有力的理论基础和新证据的推动下，包括我们实验室将胎盘印记基因表达与婴儿神经发育联系起来的工作，该项目旨在开发一种基于印记的生物标志物，可以前瞻性地预测神经行为结果，最终可用于立即识别婴儿处于危险之中，以便启动/实施早期干预。我们制定了一项多阶段研究计划，首先利用正在进行的罗德岛儿童健康研究 (RICHS) 的综合资源，该研究采用经过验证的前瞻性预测 NICU 网络神经行为量表 (NNNS) 作为新生儿神经行为的表型测量900 名新生儿的出生队列，以确定与关键神经行为指标相关的生物标志物组。然后，我们将使用已建立但独立的资源新罕布什尔州出生队列研究 (NHBCS) 来证明该生物标志物的有效性和普遍性，该研究使用与 RIHS 类似的数据收集程序。此外，尽管环境极其复杂，但我们决定重点关注胎儿接触金属的情况，特别是那些被广泛认为是神经毒素或被认为具有保护作用的金属，作为建立综合模型来检查子宫内金属之间相互关系的范例。微量金属暴露、基因组印记和新生儿神经行为结果。识别与异常神经发育或环境暴露相关的印记特征将通过查明神经行为缺陷的某些环境风险因素而具有重大的临床和公共卫生意义，或作为早期诊断工具的基础，从而为早期干预提供机会。