“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: 10610813
• 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/10610813
• 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; Population; Predisposition; Pregnant Women; Prevention; Primary Prevention; Race; Regulation; Research; Resources; Risk; Risk Factors; Role; Running; Scientist; Secure; Seminal; Shapes; System; Systems Development; Testing; Training; Umbilical Cord Blood; United States National Institutes of Health; Universities; Wheezing; Wood material; age group; 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.

项目摘要/摘要 玛丽亚·古铁雷斯（Maria Gutierrez）博士是约翰·霍普金斯大学（JHU）的儿科过敏症，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翻译 - 资助的研究计划着重于人类免疫的表观遗传和代谢调节机制 在早期生命中。她的短期目标是调查孕产妇肥胖的关联和风险增加 婴儿期下呼吸道感染（LRTI）的她在波士顿出生的2,608名儿童中的初步数据 队列（BBC）最近确定，肥胖母亲出生的婴儿的LRTI风险增加与 婴儿性别，种族，胎龄，孕产妇吸烟，平等和母乳喂养。基于这些发现， 该提议的中心假设是，孕产妇肥胖会引起胎儿表观遗传和代谢改变 破坏早期生命免疫发育，并导致LRTI在婴儿期的敏感性提高。测试这个 假设，她将利用包含全面临床信息的BBC的前瞻性数据 与DNA甲基化（DNAM）和代谢组谱（液相色谱量质量质量）相关联 在约1,000个母亲二元组中获得的光谱法（脐带血）获得。提出了两个具体目标：（1） 为了检验孕产妇肥胖改变胎儿免疫基因组（DNAM）的假设导致增加 婴儿期LRTI的敏感性； （2）测试孕产妇肥胖失调胎儿代谢的假设 与LRTI在生命的第一年的发展相关的途径。该项目完成后，博士 Gutierrez将在1）高通量的计算分析中获得基本培训和经验 人类免疫学研究中使用的数据集特别关注表观遗传学和代谢组学数据； 2） 基于DNAM的细胞反卷积的新方法，以表征细胞特异性分子表观遗传学程序 受环境的影响； 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确保独立R01级资金所需的领导技能。 Gutierrez博士将通过正式课程，讲习班，国家实现她的研究和培训目标 会议和指导研究。她获得K23奖的主要导师是创始人王王博士， JHU疾病早期起源和BBC PI的生命中心主任。王博士是一个经验丰富的 分子流行病学的导师和国际领导者做出了定义的开创性贡献 儿童健康的表观遗传学和代谢预测因素。指导团队由小儿专家组成 过敏和免疫学研究（Robert Wood博士），计算生物学（Xiumei Hong博士）和 发育免疫学（Steven Desiderio博士和Kathleen Sullivan博士）。这个培训计划和数据 由这个拟议的项目产生的，将为成为独立临床医生的基础 - 研究免疫系统发展的表观遗传和代谢调节的科学家 人类的生活及其在健康和疾病中的长期影响。