Epigenetic mechanisms of social disparities in health and development

描述（由申请人提供）：这个短期指导的高级职业发展奖的目标是为PI的研究领域增加对表观遗传学概念，方法和当前研究的理解，以他正在进行的生物发育机制的工作，这些机制是观察到的社会差异和儿童健康和发展结果不平等的基础。特别的重点将是获取关于通过表观遗传机制表达的环境影响的工作现状的核心知识，并为将这项工作扩展到调查由于不同社会影响而产生的人口样本中的表观遗传机制奠定基础。该奖项的培训部分包括六个部分：在整个培训期间，在个别会议和研究小组中与主要导师胡博士的互动；参加密歇根大学的主要研究小组，专注于这些主题；参加环境健康科学核心研究生课程，重点是环境健康中的基因组学和表观基因组学；执行一项研究项目，在现有的纵向数据库中探索社会差异的影响，以及可能的表观遗传中介，该数据库是用于研究毒性和表观遗传效应的出生队列；参加国际研究网络会议，该会议涉及社会驱动表观遗传效应研究领域的两位领军人物的工作；通过审查该领域目前的IRB协议，并与主要研究人员和IRB成员进行讨论，将PI目前对基因组学和表观基因组学研究伦理行为的熟悉程度扩展到该领域。这项短期职业发展奖励研究的具体目的是通过纵向出生队列的随访分析，探讨表观遗传机制在母亲的社会经济地位（SEP）与后代的儿童健康结果之间的关系中可能发挥的作用。尽管对SEP对儿童发育健康的影响进行了广泛的研究（Keating, 2009; Keating, in press b），但关于这些影响的运作机制仍有许多问题。其次，有大量研究表明，表观遗传机制对物理环境（如铅）中不同暴露所引起的健康结果的作用（Pilsner， Hu等，2009；Wright等，2010）。第三，有一个新兴的研究文献表明，在动物和少数人类研究中，社会环境暴露也可能导致表观遗传变化，而表观遗传变化又可能与纵向健康和发展结果有关（Szyf, McGowan, & Meaney, 2008）。目前的建议旨在验证这样一种假设，即社会地位的变化，被认为是母亲压力和压力缓冲的标志，与表观遗传标记有关，表观遗传标记已被确定与压力反应系统有关。还将分析母亲的社会地位，将其作为儿童健康和发展结果的预测因素。如果观察到的直接关系如预测的那样，表观遗传标记可以作为SEP预测儿童结局的可能中介进行研究。

DESCRIPTION (provided by applicant): This goal of this short-term mentored senior career development award is to add to PI's research areas an understanding of the concepts, methods, and current research in epigenetics to his on-going work on biodevelopmental mechanisms that underlie observed social disparities and inequalities in health and development outcomes for children and through the life course. The particular focus will be on acquiring core knowledge on the current status of work on environmental influences expressed through epigenetic mechanisms, and laying the groundwork for extending that work to investigate epigenetic mechanisms in population samples that result from differential social influences. The training component of the award includes six components: interactions with the primary mentor, Dr. Hu, throughout the training period, in individual meetings and in research groups; participation in the primary research group focusing on these topics at the University of Michigan; participation in the core graduate course in Environmental Health Sciences that focuses on genomics and epigenomics in environmental health; execution of a research project to explore the impacts of social disparities, and possible epigenetic mediation, in an existing longitudinal database, a birth cohort that has been used to study toxicity and epigenetic effects; participation in a meeting of an international research network that involves the work of two leading figures in the study of socially driven epigenetic effects; extending PI's current familiarity with the ethical conduct of research into the areas of genomics and epigenomics, through review of current IRB protocols in this area and discussions with key researchers and IRB members. The specific aim of the research to be conducted during this short-term career development award is to investigate the possible role of epigenetic mechanisms on the relationship between socioeconomic position (SEP) of the mother and child health outcomes of the offspring, through follow-up analyses of a longitudinal birth cohort. Although there has been extensive research on the effect of SEP on child developmental health (reviewed by Keating, 2009; Keating, in press b), there remain many questions about the mechanisms through which these effects operate. Second, there is a substantial body of research that indicates the role of epigenetic mechanisms on health outcomes arising from differential exposures in the physical environment, such as lead (Pilsner, Hu, et al., 2009; Wright et al., 2010). Third, there is an emerging research literature that suggests the probability that social environment exposures may also lead to epigenetic changes, which may in turn be linked to longitudinal health and development outcomes, in both animal and a few human studies (Szyf, McGowan, & Meaney, 2008). The current proposal aims to test the hyphothesis that variations in social status, which are putatively markers of maternal stress and stress buffers, are associated with epigenetic markers, which have been identified as being linked to the stress response system. Maternal social status will also be analyzed as a predictor of child health and development outcomes. If the direct relationships are observed as predicted, the epigenetic markers can be investigated as possible mediators of the SEP prediction of child outcomes. PUBLIC HEALTH RELEVANCE: The primary goal of this career development application and the included research component is to investigate epigenetic mechanisms underlying social disparities in life course health and development. Environmental effects on how genes function and are regulated have been found for a range of exposures, and these modifications of gene function can have substantial effects on subsequent health and development. Recent work has shown that the social environment can have similar epigenetic and health effects. The proposed work investigates the possible role of epigenetics in the production of social disparities in health and development. Understanding these mechanisms would provide important insights into, and possible remediation, the social determinants of population health.