Characterizing the functional genomic atlas of human placenta and unveiling the prenatal programming of early-life development

表征人类胎盘的功能基因组图谱并揭示早期生命发育的产前编程

• 批准号: 10580294
• 负责人: Jia Chen
• 金额: $ 72.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580294
• 关键词: Abnormal placentation; Address; Adult; Affect; Age; Alleles; Atlases; Automobile Driving; Biological Markers; Birth; Birth Weight; Body mass index; Cardiovascular system; Cell Nucleus; Cells; Child Health; Childhood; Cohort Studies; Communities; Complex; Data; Data Set; Development; Disease; Early Intervention; Elderly; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Evaluation; Fetal Development; Gene Expression; Genetic; Genetic Induction; Genetic Transcription; Genetic Variation; Genome; Genomics; Growth; Growth and Development function; Health; Human; Human Development; Inherited; Intervention; Investigation; Knowledge; Lead; Life; Link; Mediating; Mediation; Mediator; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Biology; National Institute of Child Health and Human Development; Neonatal; New Hampshire; Obesity; Organ; Outcome; Pathway interactions; Perinatology; Placenta; Population; Population Heterogeneity; Populations at Risk; Pregnancy; Pregnancy Outcome; Prevention strategy; Process; Protocols documentation; Proxy; Quantitative Trait Loci; RNA Splicing; Reproducibility; Research; Research Priority; Resolution; Resources; Rhode Island; Role; Signal Transduction; Solid; Stress; Structure; Systems Biology; Technology; Testing; Tissues; Translations; Variant; Work; burden of illness; cohort; design; disorder risk; early childhood; functional genomics; genetic variant; genome wide association study; health disparity; improved; in utero; innovation; insight; instrument; non-genetic; obesity in children; offspring; postnatal; predictive modeling; prenatal; programs; prospective; risk stratification; single nucleus RNA-sequencing; trait; transcriptome; transcriptome sequencing; transcriptomics

SUMMARY/ABSTRACT A substantial proportion of postnatal health, including childhood obesity and metabolic disease, is programmed in utero during fetal development. While birthweight has been linked to these outcomes, it may be only a proxy reflecting a complex interplay of genetics and environment that defines a common etiology between birthweight and later life health, and which defines the Developmental Origins of Heath and Disease (DOHaD) hypothesis. Supporting this hypothesis are a number of large, genome-wide association studies (GWAS) that have identified genetic variants associated with early life outcomes, such as birthweight and childhood obesity, body mass index and adiposity, and have demonstrated that these same variants can also impact adult cardiovascular traits and disease. Thus, early intervention, either through identifying at-risk population and/or targeting functional variations induced by genetic and environmental factors, could be highly effective in reducing overall disease burden. Our team spearheaded the placental research suggesting that the placenta may be the critical organ for much of childhood health programming. This proposal is framed on the hypothesis that the functional genome of a placenta acts as a critical and unique mediator of the in utero environment (both genetic and non-genetic) to influence birthweight and program postnatal growth and development, and such effects may occur in particular cellular components of the placenta. Leveraging the resources of three well-characterized and diverse birth cohorts in the US, we propose a rigorous integrative genomics and systems biology investigation to demonstrate the causal, mechanistic role of the placenta in postnatal health programming using state-of-the-art, post-GWAS, functional genomic investigations, including innovative use of single-nucleus RNA sequencing technology and molecular quantitative trait loci analyses (molQTL). We will build a comprehensive molecular atlas of human term placenta to identify functional molecular features that mediate birthweight GWAS hits as well as those independent of genetics, and we will build a placental transcriptomic atlas at cellular resolution to improve mechanistic understanding of the role of the placenta at the single cell level. Furthermore, we will examine prospective associations of the birthweight- related molecular features in placenta with growth trajectory, childhood obesity, BMI, and adiposity at age 5 as a model of the placenta’s role in long-term health programming. This project aligns with the research priorities of Pregnancy and Perinatology Branch of the NICHD, in defining “molecular biology processes involved in normal and abnormal placentation” as well as “genetic and epigenetic factors that adversely affect pregnancy outcomes”. Results from our study will pave the way for the development of placenta-based biomarkers to be assessed at birth for prospective risk stratification into childhood so early intervention may be implemented; they will also help identify mechanistic pathways useful in defining prevention or intervention strategies to alleviate long-term disease burden.

摘要/摘要 编程 在胎儿发育过程中的子宫内。尽管出生体重与这些结果有关，但这可能只是一个代理 反映遗传学和环境的复杂相互作用，该相互作用定义了出生体重之间的共同病因 以及后来的生活健康，并定义了健康和疾病（DOHAD）假设的发展起源。 支持这一假设的是许多具有大型全基因组关联研究（GWAS） 确定了与早期生活结果相关的遗传变异，例如出生体重和儿童肥胖，身体 质量指数和肥胖，并证明这些相同的变体也会影响成人 心血管特征和疾病。这是通过确定高危人群和/或 靶向由遗传和环境因素引起的功能变化，在 减轻总体疾病负担。我们的团队率先进行了占地研究，这表明胎盘 对于大部分儿童健康计划来说，可能是关键的器官。该建议是在 假设plapeta的功能基因组充当子宫中的关键和独特的介体 环境（遗传和非遗传）影响出生体重和计划后增长以及 发育和这种影响可能会发生在多余的特定细胞成分中。利用 在美国，三个特征良好和潜水员出生队列的资源，我们提出了一个严格的综合综合 基因组学和系统生物学研究，以证明plapeta在 使用最先进的GWAS，功能基因组研究的产后健康编程，包括 单核RNA测序技术和分子定量性状基因座分析的创新使用 （molqtl）。我们将建立人类术语pliceta的全面分子图集，以识别功能 媒体的出生体重GWA和独立于遗传学的分子特征，我们将 在细胞分辨率下建立胎盘转录组图集，以提高机械理解 单细胞水平的lopeta。此外，我们将研究出生体重的潜在关联 与生长轨迹，儿童对象，BMI和5岁时的肥胖相关分子特征AS Pleceta在长期健康计划中的作用的模型。该项目与研究的重点保持一致 NICHD的怀孕和生态学分支，定义“分子生物学过程 正常和异常放置”以及“遗传和表观遗传因素不利影响妊娠 结果”。我们的研究结果将为开发基于Plopeta的生物标志物的发展铺平道路 在出生时评估了前瞻性风险分层为儿童时期，因此可以实施早期干预； 他们还将帮助确定有助于定义预防或干预策略的机理途径 减轻长期疾病伯恩。