Epigenetic Modifications and Social Disparities in Neurodevelopmental Vulnerabili

神经发育脆弱性的表观遗传修饰和社会差异

• 批准号: 8145556
• 负责人: THOMAS W BOYCE
• 金额: $ 35.14万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8145556
• 关键词: 9 year old; Academic achievement; Address; Archives; Behavioral; Biological; Biological Process; Birth; Blood; British Columbia; Candidate Disease Gene; Child; Code; Cognitive; Communities; CpG dinucleotide; Cytosine; DNA Methylation; Data; Data Set; Databases; Detection; Development; Disadvantaged; Employee Strikes; Environment; Environmental Exposure; Enzymes; Epidemiologic Studies; Epidemiology; Epigenetic Process; Event-Related Potentials; Family; Foundations; Functional Magnetic Resonance Imaging; Gene Expression Regulation; Gene Mutation; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Health; Health Sciences; Healthcare Systems; Human Genome; Individual; Knowledge; Lateral; Learning; Life; Link; Location; Maps; Mental disorders; Methylation; Modification; Molecular; Molecular Genetics; Monoclonal Antibody R24; Mutation; Neonatal Screening; Neurobiology; Parents; Pattern; Performance at work; Plant Roots; Population; Population Database; Predisposition; Prefrontal Cortex; Process; Promoter Regions; Province; Regulation; Relative (related person); Research; Resources; Role; Sampling; Sampling Studies; Single Nucleotide Polymorphism; Site; Social Class; Spottings; Stimulus; Testing; Visual; Work; base; body-mind; design; epidemiologic data; epigenomics; experience; extrastriate; health disparity; insight; methyl group; neurodevelopment; novel; population based; population health; preconditioning; prepuberty; programs; promoter; resilience; response; social; social disparities; socioeconomics

In the PROGRAM OVERVIEW section of our parent R24 application, we argued that careful study of SES-atypical communities and individuals could yield key insights into what is arguably the most powerful, enduring and yet enigmatic association in the field of mind-body health and, more generally, the field of population health science. Why do some children thrive and flourish despite rearing experiences in blighted, disadvantaged socioeconomic conditions? Why do others founder¿developmentally, psychologically, physically¿in circumstances of wealth, abundance and unlimited resource availability? More generally, why do most children follow developmental paths staunchly typical of the social class into which they were born, while others show striking signs of atypical resilience or vulnerability? We argued that a precondition to answering such questions would be fundamentally new knowledge of the neurobiological and genetic substrates underlying SES-atypicality¿that is, how early social environmental exposures and epigenetic regulation of gene expression work together to influence a child's susceptibility v. resilience to compromised and disadvantaged social circumstances. Finally, we argued that informative studies of the biological processes underlying SES vulnerability and resilience would require genuinely population-level analysis and the capacity for strategically sampling communities of children with known socioeconomic and developmental attributes. Only population-based data will allow unbiased ascertainment of gene-environment interplay within targeted SES-typical and -atypical groups. This first of five projects advanced within an R24 application on Social Disparities in Epigenetic Regulation of Neurodevelopment thus proposes to explore the feasibility of joining social epidemiology to cutting-edge molecular genetics through the exploitation of a truly unique and largely untapped scientific resource: a set of linkable, whole-population databases from the Canadian province of British Columbia: databases that collectively access genetic, biomedical, developmental, educational, and socioeconomic information on an entire societal jurisdiction of children. The size, breadth and depth of these data¿from a province with an established and universal health care system¿proffer an unprecedented opportunity for careful, precisely crafted studies of the early biological foundations of health disparities. Our proposed Project 1¿on Epigenetic Modifications and Social Disparities in Neurodevelopmental Vulnerability¿comprises two sub-studies, with five specific aims. The first sub-study (Sub-Study A) seeks to confirm and extend a striking and potentially important finding from our prior, R21 pilot research: that prepubertal children from low SES families, relative to children from high SES families, show systematic event-related potential (ERP) deficits in lateral prefrontal cortical processing of novel stimuli. Such differences in cognitive neurodevelopment appearing within the first decade of life, if confirmed in subsequent, broader study samples, could constitute one of the biological bases of lifelong, SES-related differences in academic achievement, job performance and learning. It is indeed likely that neurobiological disparities of this kind are related to the tenacity with which social class membership generally persists¿unchanged¿over a lifetime of individual experience. The second sub-study (Sub-Study B), addresses the biological roots of SES-atypicality at an even more fundamental, molecular level and proposes to explore the practicality and scientific promise of using population-level epidemiologic data to examine differences in DNA methylation among children from varying socioeconomic strata. Sub-Study B¿by further extending epidemiologic linkages among the BC data sets and examining patterns of epigenetic modification within targeted groups of SES-atypical children¿will generate provisional but groundbreaking observations on epigenomic dissimilarities among children from distinctive social backgrounds. To our knowledge, Sub-Studies A and B would be the first to detect and codify experience-dependent, neurobiological and epigenetic changes within epidemiologic samples of young, socioeconomically diverse children.

在我们的父 R24 申请的项目概述部分中，我们认为仔细研究 SES-非典型 社区和个人可以对什么是最强大、最持久的领域产生重要见解 然而，在身心健康领域，更广泛地说，在人口领域，却存在着神秘的联系 为什么有些孩子尽管在贫困的环境中成长，却依然茁壮成长。 为什么其他人会在社会经济条件不利的情况下失败？从发育上、心理上、 身体的更一般地说，在财富、丰富和资源无限的情况下，为什么这样做？ 大多数孩子遵循他们所出生的社会阶层的典型发展道路，而 其他人表现出非典型的韧性或脆弱性的明显迹象？我们认为这是回答的先决条件？ 这些问题将是神经生物学和遗传基础的全新知识 潜在的SES非典型性¿也就是说，早期的社会环境暴露和表观遗传调控如何 基因表达共同影响儿童的易感性和抵御能力 最后，我们认为生物过程的信息研究。 潜在的社会经济地位脆弱性和复原力需要真正的人口层面分析和能力 用于对具有已知社会经济和发展特征的儿童社区进行战略性抽样。 只有基于人群的数据才能在目标范围内公正地确定基因与环境的相互作用 SES-典型群体和非典型群体。 这是 R24 应用程序中推进的五个项目中的第一个，该应用程序涉及表观遗传调控中的社会差异 因此，Neurodevelopment提出探索将社会流行病学与前沿技术相结合的可行性 通过利用真正独特且很大程度上尚未开发的科学资源来进行分子遗传学：一组 来自加拿大不列颠哥伦比亚省的可链接的全人口数据库：数据库 共同获取遗传、生物医学、发育、教育和社会经济信息 这些数据的规模、广度和深度。来自一个省份 建立全民医疗保健体系¿提供了前所未有的机会来仔细、精确地 对健康差异的早期生物学基础进行了精心研究。 我们提议的项目 1¿关于神经发育的表观遗传修饰和社会差异 漏洞¿包括两个子研究，有五个具体目标第一个子研究（子研究 A）旨在： 确认并扩展了我们之前的 R21 试点研究中一个引人注目且可能重要的发现： 与来自高社会经济地位家庭的儿童相比，来自低社会经济地位家庭的青春期前儿童表现出系统的事件相关性 外侧前额皮质处理新刺激的潜在（ERP）缺陷。 如果在后续更广泛的研究中得到证实，认知神经发育会在生命的第一个十年内出现 样本，可能构成终身的、与 SES 相关的学术差异的生物学基础之一 这种神经生物学差异确实可能存在于成就、工作表现和学习方面。 与社会阶层成员身份普遍存在的顽强程度有关。不变??一生中 个人经验。 第二个子研究（子研究 B）更加深入地探讨了 SES 非典型性的生物学根源。 基础、分子水平，并建议探索使用的实用性和科学前景 人口水平的流行病学数据来检查不同地区儿童 DNA 甲基化的差异 移动地层子研究 B¿通过进一步扩展 BC 数据集之间的流行病学联系 检查非典型 SES 儿童目标群体的表观遗传修饰模式？将生成 关于不同种族儿童表观基因组差异的临时但开创性的观察 据我们所知，子研究 A 和 B 将是第一个发现和编纂的。 年轻人的流行病学样本中依赖于经验的神经生物学和表观遗传学变化 社会多元化的孩子。