Maternal obesity, micronutrient supplementation, and epigenetic programming

 描述（由申请人提供）：这是在科罗拉多安舒茨大学医学院雅各布·弗里德曼博士的指导下申请K 01职业发展奖。K 01奖的母项目是比尔和梅林达盖茨基金会赞助的一项名为“女性优先”的随机对照试验（clinicaltrials.gov NCT 01883193）。妇女优先是第三世界（4个国际站点）的一个大型母婴纵向出生队列，正在调查营养干预的时机是否可以改善母婴结局。这个K 01奖将考察一个容易出现生长发育迟缓和肥胖的国际地点（危地马拉）。我提议的研究项目将评估妊娠前服用微量营养素补充剂（MNS）≥ 3个月（第1组）的瘦或肥胖母亲所生婴儿的脐带血（UCB）中DNA甲基化的变化，MNS开始于妊娠12周（第2组），或不补充（组3）和后代对发育不良生长（出生身长）和肥胖症（身长体重Z评分）的易感性。我的主要假设是，母亲的营养和代谢状况，怀孕前，将导致差异甲基化区域（DMR）在脐带血（UCB）与线性增长和肥胖的易感性。具体来说，我提出了3种新的方法来检查怀孕前MNS和怀孕前BMI对婴儿表观基因组的影响：SA 1）使用Roche-NimbleGen SeqCap Epi鉴定差异甲基化区域SA 2）评估新鉴定的肥胖相关亚稳态表观等位基因的DNA甲基化SA 3）使用两步孟德尔随机化来加强我假设的途径的因果推断：母亲MNS和孕前BMI → 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，以获得表观遗传学，临床和分析技能。我已经确定了安舒茨医学院的导师，他们在发展规划和肥胖（Jed Friedman博士），国际营养和儿科学（Nancy Krebs博士），表观遗传学（杨博士），生物信息学（Kenneth Jones博士）和流行病学（Dana Dabalea博士）方面都是高产的领导者。我的培训计划还将利用2位重要的国际专家i）Caroline Relton博士，他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方法以及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，杰出的顾问网络，以及创新的工具包，以促进成功过渡到独立的职业生涯，在遗传学表观遗传学和肥胖的发展起源。

 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.