SUMMARY The developing immune system in the fetus is extremely sensitive to signals from the maternal environment. Maternal pre-pregnancy (pregravid) obesity has recently emerged as one of the most significant negative regulators of the offspring's immune system development and maturation. Findings from animal models indicate maternal high fat diet-induced obesity is associated with dampened anti-microbial responses and aberrant inflammatory responses. More importantly, recent epidemiological studies have reported that neonates born to mothers with high pre-pregnancy BMI are more susceptible to severe infections such as necrotizing enterocolitis and bacterial sepsis requiring admission to the neonatal intensive care unit (NICU). We have recently shown that cord blood monocytes from babies born to obese mothers generated dampened immune responses to lipopolysaccharide (LPS), indicative of a Toll-like receptor (TLR) signaling defect. These observations provide a potential explanation for the increased susceptibility to severe infections in neonates born to obese mothers. However, the mechanisms underlying reduced host defense in offspring of obese mothers remain poorly understood. The goal of this application is to address this knowledge gap. Specically, we will define functional alterations in human neonatal monocytes induced by maternal pre-pregnancy obesity and uncover their molecular underpinnings. Moreover, we will link data from our experiments with clinical parameters collected from the pregnant mother as well as the child at birth and during the first year of life. The novelty of this application lies in the systems biology approach that integrates genomic and functional readouts with clinical metadata. Completion of the proposed experiments will reveal the molecular mechanisms that result in altered neonatal monocyte function and our findings will form a basis for developing early interventions.