“Role of Maternal Obesity in Epigenetic and Metabolic Programming and Lower Respiratory Infection Risk in Early Life”

– 母亲肥胖在表观遗传和代谢编程以及降低生命早期呼吸道感染风险中的作用 –

• 批准号: 10371252
• 负责人: MARIA JIMENA GUTIERREZ
• 金额: $ 17.08万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371252
• 关键词: Acute; Address; Affect; Antibody Formation; Asthma; Automobile Driving; Biogenesis; Biometry; Birth; Boston; Breast Feeding; Cells; Child; Childhood; Chronic; Clinical; Computational Biology; Computer Analysis; DNA; DNA Methylation; Data; Data Set; Development; Disease; Early Intervention; Educational workshop; Environment; Epigenetic Process; Foundations; Funding; Generations; Genes; Genomic Segment; Gestational Age; Goals; Health; Hospitalization; Human; Hypersensitivity; Immune; Immune system; Immunity; Immunologist; Immunology; Infant; Interdisciplinary Study; International; Knowledge; Lead; Leadership; Learning; Life; Link; Liquid Chromatography; Longitudinal cohort study; Low income; Lower Respiratory Tract Infection; Lymphocyte; Maternal Age; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methods; Methylation; Minority; Molecular; Molecular Epidemiology; Morbidity - disease rate; Mothers; Obesity; Overweight; Physicians; Plasma; Predisposition; Pregnant Women; Prevention; Primary Prevention; Race; Regulation; Research; Research Training; Resources; Risk; Risk Factors; Role; Running; Scientist; Secure; Seminal; System; Systems Development; Testing; Training; Umbilical Cord Blood; United States National Institutes of Health; Universities; Urban Population; Wheezing; Wood material; age group; base; bead chip; cohort; defined contribution; design; developmental immunology; dietary; epigenome; experience; fetal; high throughput analysis; immune function; in utero; infancy; infection risk; innovation; longitudinal analysis; maternal cigarette smoking; maternal obesity; meetings; metabolic profile; metabolome; metabolomics; methylation pattern; methylome; mortality; novel; novel strategies; obese mothers; obesity in children; parity; potential biomarker; prenatal; prevent; programs; prospective; respiratory morbidity; rheumatologist; sex; signature molecule; skills; small molecule; tandem mass spectrometry; therapeutic target

PROJECT SUMMARY/ABSTRACT Dr. Maria Gutierrez is a pediatric allergist, immunologist, and rheumatologist at Johns Hopkins University (JHU). This K23 application will allow Dr. Gutierrez to develop an innovative clinical and translational independently- funded research program focused on the mechanisms of epigenetic and metabolic regulation of human immunity during early life. Her short-term goal is to investigate the association of maternal obesity and the increased risk of lower respiratory infection (LRTI) in infancy. Her preliminary data in 2,608 children from the Boston Birth Cohort (BBC) recently identified that the increased LRTI risk in infants born to obese mothers is independent of infant sex, race, gestational age, maternal smoking, parity and breastfeeding. Based on these findings, the central hypothesis of this proposal is that maternal obesity induces fetal epigenetic and metabolic alterations that disrupt early life immune development and lead to increased LRTI susceptibility in infancy. To test this hypothesis, she will leverage the prospective data of the BBC that includes comprehensive clinical information linked to DNA methylation (DNAm) and metabolomic profiles (liquid chromatography-tandem mass spectrometry) obtained at birth (cord blood) in ~1,000 mother-infant dyads. Two specific aims are proposed: (1) To test the hypothesis that maternal obesity alters the fetal immune epigenome (DNAm) leading to increased susceptibility to LRTI in infancy; (2) To test the hypothesis that maternal obesity dysregulates fetal metabolic pathways associated with the development of LRTI in the first year of life. Upon completion of this project, Dr. Gutierrez will have acquired essential training and experience in 1) computational analysis of high-throughput datasets used in human immunology studies with a particular focus on epigenetic and metabolomics data; 2) novel methods of DNAm-based cell deconvolution to characterize cell-specific molecular epigenetic programs influenced by the environment; 3) advanced statistical design and analysis of longitudinal cohort studies; 4) leadership skills needed to lead an interdisciplinary research team and secure independent R01-level funding. Dr. Gutierrez will achieve her research and training goals through formal coursework, workshops, national meetings, and mentored research. Her primary mentor for this K23 award is Dr. Xiaobin Wang, the founder and director of the JHU Center on the Early Life Origins of Disease and PI of the BBC. Dr. Wang is an experienced mentor and international leader in molecular epidemiology who has made seminal contributions defining epigenetic and metabolic predictors of childhood health. The mentorship team is comprised of experts in pediatric allergy and immunology research (Dr. Robert Wood), computational biology (Dr. Xiumei Hong), and developmental immunology (Dr. Steven Desiderio and Dr. Kathleen Sullivan). This training plan, and the data generated from this proposed project, will provide the foundation needed to become an independent clinician- scientist studying the epigenetic and metabolic regulation of the development of the immune system in early human life and its long-term influence during health and disease.

项目概要/摘要 Maria Gutierrez 博士是约翰·霍普金斯大学 (JHU) 的儿科过敏科医生、免疫学家和风湿病学家。 该 K23 应用程序将使 Gutierrez 博士能够独立开发创新的临床和转化- 资助的研究项目侧重于人类免疫的表观遗传和代谢调节机制 在生命早期。她的短期目标是调查孕产妇肥胖与风险增加之间的关系 婴儿期下呼吸道感染（LRTI）。她对 2,608 名波士顿出生儿童的初步数据 Cohort (BBC) 最近发现，肥胖母亲所生婴儿的 LRTI 风险增加与以下因素无关： 婴儿性别、种族、胎龄、母亲吸烟、产次和母乳喂养。根据这些发现， 该提案的中心假设是，母亲肥胖会导致胎儿表观遗传和代谢改变，从而导致胎儿的表观遗传和代谢改变。 破坏生命早期的免疫发育并导致婴儿期 LRTI 易感性增加。为了测试这个 假设，她将利用 BBC 的前瞻性数据，其中包括全面的临床信息 与 DNA 甲基化 (DNAm) 和代谢组学谱（液相色谱-串联质谱 光谱测定法）在约 1,000 名母婴二人出生时获得（脐带血）。提出了两个具体目标：(1) 检验母亲肥胖会改变胎儿免疫表观基因组 (DNAm) 导致胎儿免疫表观基因组 (DNAm) 增加的假设 婴儿期对 LRTI 的易感性； (2) 检验母亲肥胖导致胎儿代谢失调的假设 与生命第一年 LRTI 发展相关的途径。该项目完成后，博士。 Gutierrez 将在 1) 高通量计算分析方面获得必要的培训和经验 用于人类免疫学研究的数据集，特别关注表观遗传和代谢组学数据； 2） 基于 DNAm 的细胞反卷积表征细胞特异性分子表观遗传程序的新方法 受环境影响； 3）纵向队列研究的高级统计设计和分析； 4） 领导跨学科研究团队并获得独立 R01 级资金所需的领导技能。 古铁雷斯博士将通过正式课程、讲习班、国家级课程来实现她的研究和培训目标 会议并指导研究。她获得K23奖项的主要导师是创始人兼创始人王晓斌博士。 JHU 生命早期疾病起源中心主任，BBC 首席研究员。王医生经验丰富 分子流行病学领域的导师和国际领导者，为定义 儿童健康的表观遗传和代谢预测因子。导师团队由儿科专家组成 过敏和免疫学研究（罗伯特·伍德博士）、计算生物学（洪秀梅博士）以及 发育免疫学（Steven Desiderio 博士和 Kathleen Sullivan 博士）。这个训练计划和数据 从这个拟议的项目中产生的，将为成为一名独立的临床医生提供所需的基础- 科学家研究早期免疫系统发育的表观遗传和代谢调节 人类生命及其在健康和疾病期间的长期影响。