Biobehavioral and Environmental Contributions to Metabolomic Profiles and Early Life Body Composition

生物行为和环境对代谢组学特征和生命早期身体成分的贡献

• 批准号: 10669244
• 负责人: Lacey W. Heinsberg
• 金额: $ 13.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669244
• 关键词: Address; Adult; Age; Alleles; Amino Acids; Beginning of Life; Behavior; Behavioral; Biochemical; Biological; Birth; Blood; Body Composition; Body mass index; Bone Density; CREB3 gene; Carbon; Cell model; Cessation of life; Child; Childhood; Chronic; Clinical; Cohort Studies; Communities; Competence; Complex; Data; Data Analyses; Data Collection; Dedications; Development; Diabetes Mellitus; Diet; Disease; Dryness; Dual-Energy X-Ray Absorptiometry; Environment; Environmental Risk Factor; Etiology; Fatty acid glycerol esters; Foundations; Future; Genetic; Genetic Variation; Genotype; Geography; Goals; Growth; Health; Infant; Intervention; Knowledge; Life; Lipids; Longevity; Maternal and Child Health; Measures; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methodology; Methods; Minor; Minority Groups; Mothers; Mus; Nonesterified Fatty Acids; Obesity; Obesity associated disease; Pacific Islander; Participant; Pathway interactions; Phase; Phenotype; Population; Pre-Clinical Model; Public Health; Quality of life; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Samoa; Samoan; Sampling; Sleep; Socioeconomic Status; Spottings; Symptoms; Thinness; Time; Training; Translating; Umbilical Cord Blood; Underrepresented Minority; Underrepresented Populations; Variant; Weight; Work; biobehavior; bone; bone mass; cardiometabolism; career development; cohort; design; ethnic diversity; experience; health equity; high risk; high risk population; improved; infancy; insight; metabolomics; nutrition; obesity in children; obesity prevention; obesity risk; phenotypic data; precision medicine; premature; prenatal; prevent; programs; racial diversity; risk variant

ABSTRACT: Childhood obesity is a significant public health problem and key risk factor for chronic conditions in adulthood. As such, there is critical need to understand childhood obesity etiology and identify opportunities for the earliest possible interventions to promote wellness across the lifespan. To that end, the objective of this proposal is to use metabolomics to better understand the foundations of variation in adiposity and body composition (e.g., fat mass, lean mass, bone mass, weight-for-age) in infancy and early life. The long-term training goal of this project is to support Dr. Heinsberg in becoming an independent investigator with a program of research dedicated to understanding and preventing obesity and improving maternal/child health. The mentored K99 will focus on participants from the nation of Samoa, as Pacific Islanders have the highest risk of obesity-related complications in the world, are one of the fastest-growing U.S. populations, but are underrepresented in health research. In Pacific Islander adults, a missense variant (rs373863828) in CREB3 Regulatory Factor (CREBRF) has an effect on body mass index larger than any other common variant. Paradoxically, the obesity-risk allele is protective against diabetes, making its functional role unclear and necessitating further mechanistic study before intervention can be considered. The obesity phenotypes of the variant are not present at birth but present clinically later in childhood. Given the results of CREBRF pre-clinical modeling and our preliminary work in infants, we hypothesize that the biological effects of the variant are present much earlier in life. To investigate this hypothesis, the K99 will draw from the Foafoaga o le Ola (“Beginning of Life”) Samoan infant cohort study. Existing resources include infant CREBRF genotype data, biospecimens, and body composition measured using dual-energy X-ray absorptiometry as well as rich behavioral/environmental data for mother-infant dyads at 1 week, 4 months, and 20 months post-birth. We will use temporal, untargeted metabolomics to increase our understanding of the biochemical mechanisms of the CREBRF variant with an emphasis on behavior/environment (Aim 1) and the foundations of body composition over the first two years of life (Aim 2). The results are expected to provide knowledge that can be translated to improved child wellness and health equity in Samoa and Pacific Islander communities in the U.S. With access to existing biospecimens and rich data from a geographically isolated birth cohort, unparalleled mentorship, and superb resources, the training environment is truly outstanding. K99 training goals to support the transition to independence include (1) metabolomic data collection/analysis, (2) metabolomic data interpretation in obese phenotypes, (3) conduct of childhood obesity research in underrepresented groups, and (4) career development. In the R00, the K99 methods will be applied to study early life adiposity in a more diverse sample (Aim 3). The insights gained will provide critical context for future work to prevent childhood obesity, promote wellness, and optimize precision medicine for public health.

摘要：儿童肥胖是慢性病的重大公共卫生问题和关键风险因素 成年。因此，迫切需要了解儿童肥胖病因并确定机会 最早可能采取的干预措施来促进整个生命周期的健康。为此，目的 建议是使用代谢组学更好地了解肥胖和身体变化的基础 婴儿期和早期生命的成分（例如脂肪质量，瘦质量，骨骼质量，体重）。长期 该项目的培训目标是支持Heinsberg博士成为一个计划的独立调查员 致力于理解和预防肥胖和改善母子/儿童健康的研究。 指导的K99将专注于萨摩亚国家的参与者，因为太平洋岛民的风险最高 世界上与肥胖相关的并发症是美国增长最快的人群之一，但是 在健康研究中的人数不足。在太平洋岛民成年人中，Creb3的错义变体（RS373863828） 调节因子（CREBRF）对大于任何其他常见变体大的体重指数具有影响。 矛盾的是，肥胖风险等位基因受到保护免受糖尿病的保护，使其功能作用不清楚，并且 需要在干预之前进行进一步的机械研究。肥胖表型 变体在出生时不存在，而是在童年后期的临床临床上存在。鉴于Crebrf前临床前的结果 建模和我们在婴儿中的初步工作，我们假设该变体的生物学作用是 出现在生活中的早期。为了研究这一假设，K99将从foafoaga o le ola中汲取 （“生命的开始”）萨摩亚婴儿队列研究。现有资源包括婴儿Crebrf基因型数据， 使用双能量X射线绝对肽和丰富的生物测量和身体组成 出生后1周，4个月和20个月的母亲二元组的行为/环境数据。我们将 使用暂时的，不靶向的代谢组学来增强我们对生化机制的理解 Crebrf变体，重点是行为/环境（AIM 1）和身体成分的基础 在生命的头两年中（目标2）。结果预计将提供可以翻译成的知识 萨摩亚和美国太平洋岛民社区的改善儿童健康和健康公平与访问 从地理上孤立的出生队列中，无与伦比的精神统治的现有生物测量和丰富的数据， 和极好的资源，培训环境确实是出色的。 K99培训目标以支持过渡 独立性包括（1）代谢组数据收集/分析，（2）肥胖中的代谢组数据解释 表型，（3）儿童肥胖研究的进行不足的群体和（4）职业 发展。在R00中，K99方法将用于研究更多样化的样本中的早期肥胖 （目标3）。获得的见解将为未来的工作提供关键背景，以防止儿童肥胖，促进 健康，并优化公共卫生的精密医学。