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

基本信息

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
项目类别：
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

项目摘要

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）是第三世界的一项大型母婴纵向出生队列（4 个国际）。该 K01 奖项将研究一个容易出现生长迟缓和肥胖的国际地点（危地马拉），该项目将评估脐带 DNA 甲基化的变化。来自瘦或肥胖母亲所生婴儿的脐带血 (UCB)，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），MNS 在妊娠 12 周时开始（第 1 组） 2) 或不补充（第 3 组）和后代易感生长迟缓（出生身长）和肥胖（身长体重 Z 值）我的主要假设是，受孕前母亲的营养和代谢状态会导致这种情况。具体来说，我提出了 3 种新方法来检查孕前 MNS 和肥胖的影响。婴儿表观基因组的孕前 BMI：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我的假设的因果推断途径：母亲 MNS 和孕前 BMI → Δ DNA 甲基化 → 婴儿结局（出生身长和身材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在发育规划和肥胖方面高产的领导者（博士）。 . Jed Friedman）、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 博士）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，他帮助罗氏创新了 SeqCap Epi 方法。 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、出色的顾问网络以及促进成功过渡到独立职业的创新工具包。翻译表观遗传学和肥胖的发育起源。