Epigenetic mechanisms of social disparities in health and development

描述(由申请者提供)：这一短期指导高级职业发展奖的目标是增加Pi的研究领域对表观遗传学的概念、方法和当前研究的理解，以及他正在进行的生物发展机制方面的工作，这些机制是观察到的儿童和整个生命过程的健康和发展结果中的社会差异和不平等的基础。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，并为扩展这项工作奠定基础，以研究不同社会影响导致的人口样本中的表观遗传机制。该奖项的培训部分包括六个部分：在整个培训期间，在个人会议和研究小组中与主要导师胡博士进行互动；参加密歇根大学以这些主题为重点的主要研究小组；参加环境健康科学的核心研究生课程，重点是环境健康中的基因组学和表观基因组学；执行一个研究项目，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调节；一个出生队列已用于研究毒性和表观遗传效应；参加一个国际研究网络的会议，该网络涉及社会驱动的表观遗传效应研究的两位领军人物的工作；通过审查该领域目前的IRB协议以及与关键研究人员和IRB成员的讨论，扩大PI目前对基因组学和表观基因组学领域研究伦理行为的熟悉程度。在这一短期职业发展奖期间进行的研究的具体目的是通过对纵向出生队列的跟踪分析，调查表观遗传机制在母亲的社会经济地位(SEP)和子女健康结果之间的可能作用。尽管关于SEP对儿童发育健康的影响已经有了广泛的研究(基廷，2009；基廷，b)，但关于这些影响的作用机制，仍然存在许多问题。其次，有大量研究表明，表观遗传机制对铅等物理环境中不同暴露产生的健康结果的作用(Pilsner，Hu等人，2009年；Wright等人，2010年)。第三，在动物和一些人类研究中，有一项新的研究文献表明，社会环境暴露也可能导致表观遗传变化，这反过来可能与纵向的健康和发育结果有关(Szyf，McGowan和Meaney，2008)。目前的建议旨在测试社会地位的变化与表观遗传标记有关的假设，社会地位的变化被认为是母亲压力和压力缓冲的标志，表观遗传标志已被确定与压力反应系统有关。还将分析产妇的社会地位，将其作为儿童健康和发展结果的预测指标。如果如预测的那样观察到直接关系，表观遗传标记可以被调查为SEP预测儿童结局的可能中介因素。 公共卫生相关性：这项职业发展申请和所包括的研究组成部分的主要目标是调查在生命过程、健康和发展过程中潜在的社会差异的表观遗传机制。环境对基因的功能和调控方式的影响已经在一系列的暴露中被发现，这些基因功能的改变可以对随后的健康和发育产生实质性的影响。最近的研究表明，社会环境可能具有类似的表观遗传和健康影响。这项拟议的工作调查了表观遗传学在造成健康和发展方面的社会差异方面可能发挥的作用。了解这些机制将为了解人口健康的社会决定因素提供重要的见解和可能的补救措施。

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.