Postdoctoral Fellowship: SPRF: Early Life Adversity Effects on DNA Methylation: Developmental Trajectories and Functional Consequences

该奖项是作为NSF社会、行为和经济学博士后研究奖学金(SPRF)计划的一部分提供的。SPRF计划的目标是为学术界、工业界或私营部门和政府的科学职业生涯培养有前途的、早期职业博士水平的科学家。SPRF奖项包括在知名科学家的赞助下进行两年的培训，并鼓励博士后研究员进行独立研究。国家科学基金会致力于促进科学界所有阶层的科学家参与其研究方案和活动，包括那些来自代表性不足的群体的科学家；博士后阶段被认为是实现这一目标的专业发展的一个重要水平。每个博士后研究员都必须解决推动各自学科领域向前发展的重要科学问题。在范德比尔特大学Amanda J.Lea博士的赞助下，这一博士后奖学金奖项支持一位研究早期生活逆境影响的早期职业科学家。众所周知，早年经历的逆境会导致持续到成年的健康后果，但将早年生活环境与晚年健康联系起来的生物学机制尚不清楚。DNA甲基化是一种表观遗传过程，可能会影响基因调控和疾病，是一种潜在的机制，通过这种机制，早期生命经验可能会嵌入生物体的生理中，从而影响以后的健康。这项研究提出了一项大规模的调查，研究早期生活中的逆境如何预测DNA甲基化和非人类灵长类猕猴体内所有主要器官系统的基因调控。非人灵长类是理解人类生物学的一个很好的比较类别，因为我们有着悠久的共同进化历史，以及我们在生理和社会行为方面的相似之处。这项研究将是迄今为止最全面的关于早期生活逆境如何影响非人类灵长类动物DNA甲基化的系统范围的询问，这将有助于我们理解灵长类(包括人类)如何感知和应对社会生态挑战，以及这些经历如何产生行为和健康差异。在美国，三分之一的儿童在童年期间经历过不利事件，其中经历逆境的比例更高。通过对童年逆境如何改变生理学的更多了解，这项研究旨在为未来发展改善受影响最严重社区个人生活的医疗干预措施奠定基础。对于灵长类物种，早期生活逆境(ELA)与较差的成人健康和进化适应性的替代指标，如寿命、繁殖率和后代存活率有关。该项目旨在更好地了解早期生活中经历的困难如何影响DNA甲基化(DNaM)，dNaM是一种表观遗传基因调控机制，参与调节早期生活环境和成年表型之间的关系。虽然已知dNaM和ELA之间的相关性，但尚未对ELA相关的dNaM模式进行系统范围的彻底表征。此外，dNaM在多大程度上驱动或抑制了基因表达，这是影响表型的一个必要的前驱指标，这一点高度可变，也知之甚少。为了解决这些知识上的差距，该项目将利用来自293只自由放养猕猴的行为、人口统计学和基因组数据，并将调查ELA相关dNaM在跨越所有主要器官系统的10个不同组织中的存在和发育轨迹。此外，该项目将通过1)评估染色质的可及性和ELA相关部位附近基因的表达，以及2)使用大规模平行报告试验来实验测试特定位点的dNaM对基因表达的影响，从而确定ELA相关的dNaM在3种组织(血液、肾脏和肺)中的功能重要性。这项研究将构成迄今为止在非人类灵长类动物中对ELA相关dNaM进行的最全面的系统范围的询问，并将第一次将特定于基因位点的dNaM数据与体内基因调控测量和能够测试ELA背景下因果甲基化-表达关系的实验分析配对。这里提出的创新方法将为自然生活的灵长类动物感知和应对社会生态挑战的表观遗传机制提供新的见解，并将提供关于社会生态环境如何“深入”影响与人类进化和健康相关的表型变化的洞察。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award was provided as part of NSF's Social, Behavioral and Economic Sciences Postdoctoral Research Fellowships (SPRF) program. The goal of the SPRF program is to prepare promising, early career doctoral-level scientists for scientific careers in academia, industry or private sector, and government. SPRF awards involve two years of training under the sponsorship of established scientists and encourage Postdoctoral Fellows to perform independent research. NSF seeks to promote the participation of scientists from all segments of the scientific community, including those from underrepresented groups, in its research programs and activities; the postdoctoral period is considered to be an important level of professional development in attaining this goal. Each Postdoctoral Fellow must address important scientific questions that advance their respective disciplinary fields. Under the sponsorship of Dr. Amanda J. Lea at Vanderbilt University, this postdoctoral fellowship award supports an early career scientist investigating the effects of early life adversity. Adversity experienced in early life is known to have health consequences lasting into adulthood, however the biological mechanism connecting early life environment to later life health is unknown. DNA methylation, an epigenetic process that can impact gene regulation and disease, is one potential mechanism by which early life experiences may become embedded within an organism’s physiology to impact health later in life. This research proposes a large-scale investigation of how early life adversity predicts DNA methylation and gene regulation throughout all major organ systems of the body in a non-human primate, the rhesus macaque. Non-human primates are an excellent comparative taxa for understanding human biology due to our long shared evolutionary history and our similarities in physiology and social behavior. This study will be the most comprehensive systems-wide interrogation of how early life adversity impacts DNA methylation in a non-human primate to date, which will aid in our understanding of how primates (including humans) sense and respond to socio-ecological challenges and how behavioral and health disparities emerge from these experiences. One third of children in the US experience an adverse event during childhood, and adversity is disproportionately experienced. By forming a greater understanding of how childhood adversity alters physiology, this study aims to lay the groundwork for future development of medical interventions improving the lives of individuals from the most affected communities.Across primate species, early life adversity (ELA) is associated with poor adult health and proxies of evolutionary fitness, such as longevity, reproductive rate, and offspring survival. This project aims to better understand how hardship experienced during early life influences DNA methylation (DNAm), an epigenetic gene regulatory mechanism that has been implicated in mediating the relationship between early life environment and adult phenotype. Although there are known correlations between DNAm and ELA, there has yet to be a thorough systems-wide characterization of ELA-associated DNAm patterns. Moreover, the extent to which DNAm drives or suppresses gene expression, a necessary pre-cursor for impacting phenotype, is highly variable and poorly understood. To address these gaps in knowledge, this project will leverage behavioral, demographic, and genomic data from 293 free-ranging rhesus macaques and will investigate the presence and developmental trajectory of ELA-associated DNAm in 10 different tissues spanning all major organ systems. Furthermore, this project will determine the functional importance of ELA-associated DNAm in 3 tissues (blood, kidney, and lung) by 1) assessing chromatin accessibility and the expression of genes near ELA-associated sites, and 2) using massively parallel reporter assays to experimentally test the impact of locus-specific DNAm on gene expression. This study will constitute the most comprehensive systems-wide interrogation of ELA-associated DNAm in a non-human primate to date and will be the first to pair locus-specific DNAm data with both in vivo measurements of gene regulation and experimental assays capable of testing for causal methylation- expression relationships in the context of ELA. The innovative approaches proposed here will provide new insight into the epigenetic mechanisms that allow naturally living primates to sense and respond to socio-ecological challenges, and will provide insight into how the socio-ecological environment “gets under the skin” to influence phenotypic variation relevant to human evolution and health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.