Inter-generational Link of Cardio-Metabolic Risk: Integrate Multi-OMICs with Birth Cohort

心脏代谢风险的代际联系：将多组学与出生队列相结合

• 批准号: 9915936
• 负责人: Liming Liang
• 金额: $ 65.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915936
• 关键词: 21 year old; Address; Adverse effects; Affect; Age; Animal Model; Anti-Inflammatory Agents; Antioxidants; Biological Process; Birth; Blood; Blood Pressure; Boston; Child; Clinical; Clinical Data; Cohort Studies; DNA Methylation; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endocrine Disruptors; Endothelium; Environment; Epigenetic Process; Folic Acid; Funding; Future; Future Generations; Genes; Genome; Grain; Growth; Health; Homocysteine; Human; Hypertension; Individual; Infant; Inflammation; Insulin Resistance; Intervention; Lead; Life; Link; Low income; Malnutrition; Mediating; Minority; Mothers; Multiomic Data; Multivitamin; Nature; Newborn Infant; Nucleic Acids; Nutrient; Obesity; Outcome; Overweight; Pathway interactions; Play; Population; Prediabetes syndrome; Pregnancy; Pregnant Women; Prevention; Process; Property; Public Health; Recommendation; Reproductive Health; Research; Resources; Risk; Risk Assessment; Role; Technology; Time; Umbilical Cord Blood; United States National Institutes of Health; Uterus; Vitamin B Complex; Woman; blood glucose regulation; cardiometabolic risk; cardiometabolism; cardiovascular health; cell growth; cohort; critical developmental period; epidemiologic data; epigenetic regulation; epigenetic variation; epigenome; fetal; fortification; genetic variant; genome wide methylation; genome-wide; health disparity; high risk; human study; improved; in utero; insight; insulin signaling; intergenerational; lipid biosynthesis; maternal obesity; metabolome; methylation pattern; multiple omics; next generation; nutrition; obesity risk; offspring; prenatal; prospective; repaired; reproductive; success

Abstract More than half of U.S. mothers entered pregnancy with overweight or obesity (OWO); maternal obesity is considered a major determinant of the next generations' OWO risk.7 A similar inter-generational link was observed for maternal hypertensive disorders before and during pregnancy. This inter-generational link may originate in utero and amplify the cardio- metabolic risk in current and future generations. However, questions remain about what the underlying mechanisms are and what can be done to mitigate the adverse effects of maternal cardio-metabolic disorders on offspring health. We propose to leverage the exceptional resources of the Boston Birth Cohort (BBC), one of the largest and longest U.S. high-risk urban low-income minority birth cohorts, to investigate the inter-generational link of cardio-metabolic outcomes and the role of maternal folate/B12 nutrition (modifiable early life factors), and to explore plausible epigenetic underpinnings. Furthermore, by combining fetal multi-omics data (genome, epigenome, and metabolome) with maternal and fetal epidemiological and clinical data, we seek to more precisely characterize newborns' future risk for the development of adverse cardio-metabolic outcomes up to age 21 years. Our proposal has a strong scientific premise. Both animal models and human studies implicate the intrauterine period as a critical time for the establishment of epigenetic variability. Epigenetic regulation has been implicated in a range of important biological functions, including adipogenesis, glucose homeostasis, inflammation, and insulin signaling. As such, fetal epigenetic mechanisms are critical for understanding an inter-generational link of cardio- metabolic disorders. However, currently there is no adequately powered prospective birth cohort study to assess the role of the fetal epigenome (using the latest profiling technology) along with maternal folate/B12 status in inter-generational cardio-metabolic risk in U.S. populations. Our proposal is also supported by promising preliminary data from the BBC, indicating that maternal folate status influences offspring DNA methylation and cardio-metabolic outcomes and mitigates the adverse effects of maternal cardio-metabolic disorders on offspring health. Successful completion of this study will improve our understanding of inter-generational cardio-metabolic risk and lead to a new paradigm for early prediction and prevention to halt or reverse the vicious inter-generational cycle, beginning at critical developmental windows when interventions may have the greatest impact on improving life-long health and reducing health disparities in current and future generations.

抽象的 超过一半的美国母亲患有超重或肥胖症（OWO）； 孕产妇肥胖被认为是下一代OWO风险的主要决定因素。7A 在前后，观察到类似的代际联系 怀孕期间。这种代际联系可能起源于子宫，并扩大心脏 - 当前和后代的代谢风险。但是，关于什么 潜在的机制是以及可以采取什么措施来减轻母体的不利影响 后代健康的心脏代谢疾病。 我们建议利用波士顿出生队列（BBC）的特殊资源， 美国最大，最长的高风险城市低收入少数族裔人群，调查 心脏代谢结果的代际联系和母体叶酸/B12营养的作用 （可修改的早期生命因素），并探索合理的表观遗传基础。此外， 通过将胎儿多词数据（基因组，表观基因组和代谢组）与母体和母体和 胎儿流行病学和临床数据，我们寻求更精确地描述新生儿的未来 发展不良心脏代谢结果的风险长达21岁。 我们的提议具有强大的科学前提。动物模型和人类研究 将宫内的时期暗示是建立表观遗传变异性的关键时期。 表观遗传调节与一系列重要的生物学功能有关，包括 掺杂，葡萄糖稳态，炎症和胰岛素信号传导。因此，胎儿 表观遗传机制对于理解心脏的代际联系至关重要 代谢障碍。但是，目前还没有足够的动力前瞻性出生队列 研究评估胎儿表观基因组（使用最新分析技术）的作用的研究 美国人口中代代二氧化代谢风险的母体叶酸/B12状态。我们的 提案也得到了BBC的有希望的初步数据的支持，表明 母体叶酸状况影响后代DNA甲基化和心甲基化结果 并减轻母体心脏代谢障碍对后代健康的不利影响。 这项研究的成功完成将提高我们对世代间的理解 有氧代谢风险并导致新的范式，以预测和预防停止或 逆转恶性的代际周期，从关键的发育窗口开始 干预措施可能对改善终身健康和降低健康的影响最大 当前和后代的差异。