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

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.