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：
9455672
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/9455672
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 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 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 control trial 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 obese mothers 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（由应用程序提供）：这是科罗拉多州安索斯大学雅各布·弗里德曼（Jacob Friedman）的心态下的K01职业发展奖的申请。该K01奖的母公司项目是一项法案，梅琳达·盖茨基金会赞助的随机对照试验名为女性First（ClinicalTrials.gov nct01883193）。妇女首先是第三世界（4个国际地点）的大型母亲纵向出生队列，该人正在研究营养干预的时机是否可以改善孕产妇和婴儿的结果。该K01奖将研究一个容易发生增长和肥胖的国际网站（危地马拉）。我提出的研究项目将评估脐血血液（UCB）中DNA甲基化的变化，来自概念前3个月（ARM 1）的婴儿出生的婴儿或肥胖的母亲，他们在≥3个月之前≥3个月，以12周的妊娠（ARM 2）和不补充（ARM 3）的速度（ARM 3），untsptriptation（Arm 3）开始（重量的z得分）。我的主要假设是，孕妇的营养和代谢状态在受孕之前将导致与线性生长和对肥胖症易感性有关的脐带血（UCB）的甲基化区域（DMR）。具体而言，我提出了3种新的方法，以检查预孕Mn和孕前BMI对婴儿表观基因组的影响：SA1）使用Roche-NimbleGen Seqcap Epi-Sa2鉴定不同的甲基化区域-NimbleGen Seqcap Epi SA2）评估新鉴定的肥胖型epialsabil Ca3）的甲基化的DNA甲基化2）我假定的途径的推断：孕产妇MN和孕前BMI→∆ DNA甲基化→婴儿结果（出生时间和体重），由于经验有限的大型临床同伙经验评估表观遗传学，我设计了一个特定的训练计划来获得表观遗传学，临床和分析技能。我在安索斯医学校园（Anschutz Medical Campus）确定了导师，他们是开发编程和肥胖症（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（Kenth Jones）（Kenth Jones）（Kenth Jones）和Epidemiology（Epidemiology（Drabemiole））。我的培训计划还将利用2位主要的国际专家i）Caroline Relton博士，他已经开创了2步孟德尔随机化，ii）John博士很大，他曾与Roche-Nimblegen以及许多其他相关的相关遗传学相关的赞誉，帮助创新了Seqcap Epi方法。我的培训计划包括最先进的表观遗传分析工具，出色的顾问网络以及创新的工具套件，以促进成功过渡到翻译表观遗传学和肥胖的发展起源的独立职业。