Maternal obesity, micronutrient supplementation, and epigenetic programming

孕产妇肥胖、微量营养素补充和表观遗传编程

• 批准号: 9249576
• 负责人: Sarah Jean Borengasser
• 金额: $ 13.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249576
• 关键词: Address; Bioinformatics; Biological Markers; Biology; Birth; Birth length; Blood; Body Weight; Career Choice; Cells; Child; Child Development; Clinical; Colorado; Comorbidity; Conceptions; DNA Methylation; DUSP22 gene; Data; Developing Countries; Development; Diet; Dietary Intervention; Disease; Disease susceptibility; Enhancers; Ensure; Environment; Epidemiology; Epigenetic Process; Exhibits; Exposure to; Famines; Fetal Growth; Foundations; Genetic; Genome; Growth; Growth and Development function; Guatemala; Health; Heterogeneity; Hypermethylation; Impairment; Infant; Infant Health; Insulin Resistance; International; K-Series Research Career Programs; Lead; Length; Life; Malnutrition; Maternal Exposure; Maternal and Child Health; Measurement; Measures; Mediating; Medical; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolism; Methodology; Methods; Methylation; Micronutrients; Mothers; NCOR2 gene; Nursery Schools; Nutritional; Nutritional status; Obesity; Outcome; Overweight; Pathogenesis; Pathway interactions; Pediatrics; Phenotype; Population; Predisposition; Pregnancy; Proxy; Randomized; Randomized Controlled Trials; Recommendation; Research Project Grants; Risk; Role; Silver; Site; Specificity; Starvation; Supplementation; Testing; Thinness; Time; Tissues; Training; Umbilical Cord Blood; Universities; Variant; Weight; Weight Gain; Woman; Yang; aged; arm; base; bisulfite; career; cohort; cost effectiveness; disorder risk; epigenome; epigenomics; experience; experimental study; fetal; global health; improved; in utero; infant outcome; innovation; low and middle-income countries; maternal obesity; methylation pattern; mother nutrition; novel; novel strategies; nutrition; obesity in children; obesity risk; offspring; parent project; postnatal; prenatal; prenatal exposure; prevent; public health relevance; skills; tool

 DESCRIPTION (provided by applicant): This is an application for a K01 Career Development Award under the mentorship of Dr. Jacob Friedman at the University of Colorado Anschutz - Medical Campus. The parent project for this K01 award is a Bill and Melinda Gates Foundation-sponsored randomized control trial called Women First (clinicaltrials.gov NCT01883193). Women first is a large mother-infant longitudinal birth cohort in the 3rd world (4 international sites) that is investigating whether timing of nutritional intervention can improve maternal and infant outcomes. This K01 award will examine one international site (Guatemala) that is prone to both growth stunting and obesity. My proposed research project will assess changes in DNA methylation in umbilical cord blood (UCB) from infants born to lean or obese mothers who consumed micronutrient supplementation (MNS) for ≥ 3 months prior to conception (Arm 1), MNS commenced at 12 wk gestation (Arm 2), or no supplementation (Arm 3) and offspring susceptibility for stunted growth (birth length) and obesity (weight-for-length Z-score). My primary hypothesis is that maternal nutritional and metabolic status, prior to conception, will result in differentially methylation regions (DMRs) in umbilical cord blood (UCB) associated with linear growth and susceptibility to obesity. Specifically, I propose 3 novel approaches to examine the effects of pre-conception MNS and pre-pregnancy BMI on the infant epigenome: SA1) Identification of differentially methylated regions using Roche - NimbleGen SeqCap Epi SA2) Assessing DNA methylation of newly identified obesity-associated metastable epialleles SA3) Use 2-step Mendelian Randomization to strengthen causal inference of my postulated pathway: Maternal MNS & pre-pregnancy BMI → ∆ DNA methylation → infant outcome (birth length & body weight) Due to limited experience assessing epigenetics in large clinical cohorts, I have devised a specific training plan to acquire epigenetic, clinical, and analytical skills. I hve identified mentors at Anschutz Medical Campus who are highly productive leaders in developmental programming and obesity (Dr. Jed Friedman), international nutrition and pediatrics (Dr. Nancy Krebs), epigenetics (Dr. Ivana Yang), bioinformatics (Dr. Kenneth Jones), and epidemiology (Dr. Dana Dabalea). My training plan will also take advantage of 2 key international experts i) Dr. Caroline Relton, who has pioneered 2-step Mendelian randomization, and ii) Dr. John Greally, who has helped innovate the SeqCap Epi methodology with Roche-NimbleGen as well as numerous other epigenetic-related accolades. My training plan encompasses cutting edge epigenetic analysis tools, an outstanding network of advisors, and an innovative tool-kit to facilitate a successful transition to an independent career in translatioal epigenetics and the developmental origins of obesity.

 描述（由申请人提供）：这是在科罗拉多大学安舒茨分校医学校区 Jacob Friedman 博士的指导下申请 K01 职业发展奖。该 K01 奖项的母项目是比尔和梅琳达·盖茨基金会赞助的名为“女性优先”的随机对照试验 (clinicaltrials.gov NCT01883193)。 “女性优先”是第三世界（4 个国际地点）的一个大型母婴纵向出生队列，正在研究营养干预的时机是否可以改善母婴结局。该 K01 奖项将审查一个容易出现生长迟缓和肥胖的国际地点（危地马拉）。我提出的研究项目将评估瘦或肥胖母亲所生婴儿的脐带血 (UCB) DNA 甲基化变化，这些母亲在受孕前 ≥ 3 个月服用微量营养素补充剂 (MNS)（第 1 组）、妊娠 12 周开始补充微量营养素（第 2 组）或不补充（第 3 组），以及后代对生长发育不良（出生身长）和肥胖的易感性 （长度重量 Z 分数）。我的主要假设是，受孕前母亲的营养和代谢状态将导致脐带血（UCB）中出现与线性生长和肥胖易感性相关的差异甲基化区域（DMR）。具体来说，我提出了 3 种新方法来检查受孕前 MNS 和孕前 BMI 对婴儿表观基因组的影响： SA1) 使用 Roche - NimbleGen SeqCap Epi 识别差异甲基化区域 SA2) 评估新发现的肥胖相关亚稳态表观等位基因的 DNA 甲基化 SA3) 使用两步孟德尔随机化来加强因果关系 我的假设路径的推论：母亲 MNS 和孕前 BMI → Δ DNA 甲基化 → 婴儿结局（出生身长和体重） 由于在大型临床队列中评估表观遗传学的经验有限，我设计了一个具体的培训计划来获得表观遗传学、临床和分析技能。我在安舒茨医学校区找到了一些导师，他们是发育规划和肥胖症（杰德·弗里德曼博士）、国际营养和儿科（南希·克雷布斯博士）、表观遗传学（伊万娜·杨博士）、生物信息学（肯尼思·琼斯博士）和流行病学（达纳·达巴利亚博士）方面卓有成效的领导者。我的培训计划还将利用 2 位重要的国际专家：i) Caroline Relton 博士，她是两步孟德尔随机化的先驱；ii) John Greally 博士，他帮助 Roche-NimbleGen 创新了 SeqCap Epi 方法，并获得了许多其他表观遗传学相关的荣誉。我的培训计划包括尖端的表观遗传学分析工具、优秀的顾问网络和创新的工具包，以促进成功过渡到翻译表观遗传学和肥胖发育起源方面的独立职业。