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

项目摘要/摘要 玛丽亚·古铁雷斯博士是约翰·霍普金斯大学(JHU)的儿科过敏学家、免疫学家和风湿病专家。 这款K23应用程序将使古铁雷斯博士能够独立开发创新的临床和翻译- 受资助的研究计划侧重于人类免疫的表观遗传和代谢调节机制 在生命的早期。她的短期目标是调查母亲肥胖与风险增加之间的联系 婴儿时期的下呼吸道感染(LRTI)。她在波士顿出生的2608个孩子中的初步数据 英国广播公司(BBC)最近发现，肥胖母亲所生婴儿的LRTI风险增加与 婴儿性别、种族、胎龄、母亲吸烟、产次和母乳喂养。基于这些发现， 这一建议的中心假设是，母亲肥胖会导致胎儿表观遗传和代谢改变， 扰乱早期生命免疫发育，并导致婴儿期LRTI易感性增加。为了测试这一点 假设，她将利用BBC的预期数据，其中包括全面的临床信息 与DNA甲基化(DNaM)和代谢组谱(液-质联用)相关 出生时(脐带血)在约1,000对母婴中获得)。提出了两个具体目标：(1) 为了验证母亲肥胖会改变胎儿免疫表观基因组(DNaM)从而导致 婴儿对LRTI的易感性；(2)检验母亲肥胖导致胎儿代谢紊乱的假设 在生命的第一年与LRTI发展相关的途径。在这个项目完成后，Dr。 古铁雷斯将在1)高通量的计算分析方面获得基本的培训和经验 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的细胞去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)纵向队列研究的先进统计设计和分析；4) 领导跨学科研究团队和获得独立的R01级资金所需的领导技能。 古铁雷斯博士将通过正式的课程、研讨会、国家 会议和有指导的研究。她这个K23奖项的主要导师是王晓斌博士，创始人和 英国广播公司JHU疾病和PI早期生命起源中心主任。王医生是一位经验丰富的医生。 分子流行病学的导师和国际领导者，他在定义 儿童健康的表观遗传和代谢预测因子。指导小组由儿科专家组成。 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(史蒂文·德西德里奥博士和凯瑟琳·沙利文博士)。这份培训计划和数据 从这个拟议的项目中产生的，将提供成为独立临床医生所需的基础- 研究早期免疫系统发育的表观遗传和代谢调节的科学家 人类生命及其在健康和疾病期间的长期影响。

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.