Early life environmental effects: molecular mechanisms and inter-individual variation

生命早期环境影响：分子机制和个体差异

• 批准号: 10707487
• 负责人: Amanda Lea
• 金额: $ 39.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707487
• 关键词: Adult; African; Amerindian; Biological Assay; Bolivia; Complement; Complex; DNA Methylation; Data; Data Set; Development; Elderly; Environment; Gene Expression; Gene Expression Regulation; Genetic; Genetic Variation; Genotype; Health; Human; Individual; Intervention; Kenya; Knowledge; Life; Life Experience; Life Style; Link; Marketing; Mediating; Methods; Molecular; Outcome; Pattern; Physically Challenged; Physiology; Play; Population; Predictive Factor; Predisposition; Process; Regulator Genes; Regulatory Element; Research; Resources; Role; Stimulus; Testing; Underserved Population; Urbanization; Variant; Work; cohort; early life exposure; effective intervention; experience; genome-wide; high risk; improved; insight; inter-individual variation; programs; resilience; social; trait

Project Summary Early life environments can have profound and long-lasting effects on human health, yet the mechanistic basis of these effects remain poorly understood as do the factors that explain inter-individual variation. These gaps in knowledge severely limit our ability to both predict susceptible individuals and to develop effective intervention strategies. At the molecular level, early life effects on later life health are thought to be mediated by stable changes in gene regulation. However, many gene regulatory elements are responsive to environmental stimuli throughout life, making it challenging to isolate the effects of early life conditions or to understand their stability, especially when within-lifetime environmental variation is absent or longitudinal data are not available. My research program aims to overcome these challenges by working with two subsistence-level groups: 1) the Turkana of Kenya, who are experiencing rapid lifestyle change such that early life and adult conditions are largely decoupled and 2) the Tsimane of Bolivia, who have been followed longitudinally for decades. In both groups, I will generate genome-wide gene regulatory datasets (DNA methylation, gene expression) paired with information on environmental experiences and health, allowing me to identify the mechanisms that embed early life exposures into lifelong physiology. I will also generate genome-wide genotype data for each individual, in order to ask whether genetic variation predicts sensitivity versus resilience to early life challenges at the gene regulatory level. Finally, I will complement this field-based, observational work with lab-based methods capable of testing for causal connections between 1) DNA methylation and gene expression and 2) genotype and environmentally-induced gene expression, both in high-throughput. In doing so, this project will uncover the gene regulatory mechanisms that mediate early life effects on health, as well as the degree to which these relationships are modified by genetic variation. By working “in the field” and “in the lab”, the proposed work will inform our understanding of developmental and environmental processes in natural human populations as well as causal mechanisms. More broadly, the proposed projects will link a major global phenomenon—increasing urbanization and market-integration—with gene regulatory processes and health in two understudied and underserved populations (Africans and Amerindians). It will also generate new methods and resources that will inform our understanding of the general patterns of genotype x environment interactions in human complex traits.

项目摘要 早期生活环境对人类健康有深远而持久的影响，但其机制基础 对这些影响的理解仍然很少，解释个体间差异的因素也是如此。这些差距在 知识严重限制了我们预测易感个体和制定有效干预措施能力 战略布局在分子水平上，早期生命对晚年健康的影响被认为是由稳定的 基因调控的变化。然而，许多基因调控元件对环境刺激有反应 这使得分离早期生活条件的影响或了解其稳定性具有挑战性， 特别是在不存在寿命期内环境变化或没有纵向数据的情况下。我 研究计划旨在通过与两个维持生计的群体合作来克服这些挑战：1） 肯尼亚图尔卡纳人，他们正在经历快速的生活方式变化，因此早期生活和成年条件在很大程度上 脱钩和2）玻利维亚的Tsimane，他们已经纵向跟踪了几十年。在两组中，我 将生成与信息配对的全基因组基因调控数据集（DNA甲基化，基因表达） 关于环境经验和健康，让我能够确定嵌入早期生命的机制， 接触到终生生理学。我还将生成每个个体的全基因组基因型数据， 询问基因变异是否可以预测基因对早期生命挑战的敏感性和弹性， 监管层面。最后，我将补充这一领域为基础的，观察工作与实验室为基础的方法能够 测试1）DNA甲基化和基因表达之间的因果关系，2）基因型和 环境诱导的基因表达，两者都是高通量的。在此过程中，该项目将揭示基因 调节机制，介导早期生活对健康的影响，以及在何种程度上，这些 关系是由遗传变异改变的。通过“实地”和“实验室”工作，拟议的工作将 也为我们理解自然人群的发展和环境过程提供了信息， 作为因果机制。更广泛地说，拟议的项目将把一个主要的全球现象联系起来， 城市化和市场一体化-基因调控过程和健康在两个研究不足， 服务不足的人口（非洲人和美洲印第安人）。它还将产生新的方法和资源， 为我们理解人类复杂性状中基因型x环境相互作用的一般模式提供了信息。