Maternal obesity, micronutrient supplementation, and epigenetic programming

 描述(由申请人提供)：这是在雅各布·弗里德曼博士的指导下，科罗拉多大学安舒茨医学院K01职业发展奖的申请。该K01奖的母项目是比尔和梅林达·盖茨基金会赞助的随机对照试验，名为女性优先(Clinicaltrials.gov NCT01883193)。妇女优先是第三世界(4个国际地点)的一个大型母婴纵向出生队列，正在调查营养干预的时机是否可以改善母婴结局。这个K01奖将考察一个国际地点(危地马拉)，它容易出现生长发育迟缓和肥胖。我提议的研究项目将评估瘦削或肥胖母亲在受孕前3个月补充微量营养素(≥)(第1组)、怀孕12周开始补充微量营养素(第2组)或不补充(第3组)时开始补充微量营养素的婴儿脐带血(UCB)中DNA甲基化的变化，以及后代生长发育迟缓(出生长度)和肥胖(Z评分体重)的易感性。我的主要假设是，在怀孕之前，母亲的营养和代谢状态将导致脐带血(UCB)中与直线生长和肥胖易感性相关的不同甲基化区域(DMRS)。具体地说，我提出了3种新的方法来检验怀孕前MNS和孕前体重指数对婴儿表观基因组的影响：SA1)使用Roche-NimbleGen SeqCap Epi SA2)识别差异甲基化区域2)评估新发现的肥胖相关亚稳定表观等位基因SA3)使用两步孟德尔随机化来加强对我假设的路径的因果推断：母亲MNS和孕前BMI→∆DNA甲基化→婴儿结局(出生长度和体重)由于在大型临床队列中评估表观遗传学的经验有限，我制定了一项具体的培训计划，以获得表观遗传学、临床和分析技能。我已经在安舒茨医学院找到了在发展规划和肥胖(Jed Friedman博士)、国际营养和儿科(Nancy Krebs博士)、表观遗传学(Ivana Yang博士)、生物信息学(Kenneth Jones博士)和流行病学(Dana Dabalea博士)方面高效的领导者。我的培训计划还将利用两位关键的国际专家：i)Caroline Relton博士，他开创了孟德尔两步随机化；ii)John Gally博士，他帮助创新了SeqCap Epi方法，罗氏-NimbleGen以及许多其他与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，一个杰出的顾问网络，以及一个创新的工具包，以促进成功过渡到翻译表观遗传学和肥胖的发育起源的独立职业生涯。

 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.