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 很大一部分产后健康，包括儿童肥胖和代谢疾病，都是经过编程的 虽然出生体重与这些结果有关，但它可能只是一个替代指标。 反映了遗传和环境的复杂相互作用，定义了出生体重之间的共同病因 和以后的生活健康，并定义了健康和疾病的发育起源（DOHaD）假说。 支持这一假设的是许多大型全基因组关联研究（GWAS），这些研究 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，并已证明这些相同的变异也会影响成人 因此，通过识别高危人群和/或进行早期干预。 针对由遗传和环境因素引起的功能性变异，可能非常有效 我们的团队率先进行了胎盘研究，表明胎盘可以减少总体疾病负担。 可能是许多儿童健康规划的关键机构。 假设胎盘的功能基因组是子宫内胚胎发育的关键且独特的调节者 环境（遗传和非遗传）影响出生体重并规划产后生长和 发育，并且这种影响可能发生在胎盘的特定细胞成分中。 凭借美国三个特征鲜明且多样化的出生群体的资源，我们提出了严格的综合 基因组学和系统生物学研究证明胎盘在 使用最先进的 GWAS 后功能基因组研究进行产后健康规划，包括 创新运用单核RNA测序技术和分子数量性状位点分析 (molQTL)。我们将建立一个全面的人类足月胎盘分子图谱来鉴定功能。 介导出生体重 GWAS 命中的分子特征以及那些独立于遗传学的分子特征，我们将 建立细胞分辨率的胎盘转录组图谱，以提高对胎盘转录组作用的机制理解 此外，我们将研究出生体重的前瞻性关联。 胎盘中与生长轨迹、儿童肥胖、BMI 和 5 岁时肥胖相关的分子特征 胎盘在长期健康规划中的作用模型与研究重点相一致。 NICHD 妊娠和围产期学分会在定义“涉及 正常和异常胎盘”以及“对怀孕产生不利影响的遗传和表观遗传因素” 我们的研究结果将为基于胎盘的生物标志物的开发铺平道路。 在出生时评估儿童期的前瞻性风险分层，以便实施早期干预； 它们还将帮助确定有助于确定预防或干预策略的机制途径 减轻长期疾病负担。