Early Life Stress, Cellular Vulnerability, and the Developmental Programming of Metabolic Disease

About This Grant

PROJECT SUMMARY Early life stress (ELS), particularly during fetal development, is a critical risk factor for long-term health, including obesity and metabolic disorders. This project investigates how prenatal stress exposure is biologically embedded, leading to increased vulnerability to abdominal adiposity and metabolic dysfunction. Our long-term goal is to eluci- date cellular and molecular pathways that mediate the developmental origins of metabolic disease, supporting early identification and prevention strategies for at-risk children. Despite known associations between ELS and adult dis- ease, current research is limited by inconsistent findings in early life, inadequate biomarkers of fetal stress exposure, and poor measurement of adiposity in infants. Traditional reliance on weight-based metrics fails to capture fat dis- tribution, which is key to metabolic risk. Moreover, stress exposure during pregnancy is typically estimated from basal circulating biomarkers, neglecting dynamic physiological stress responses. To address these gaps, we employ a translational, multi-level design integrating basic science and clinical research. Using umbilical-derived mesenchy- mal stromal cells (MSCs) from human newborns, we will model individualized cellular vulnerability to ELS. In par- allel, we will track in vivo adipose development using serial MRI assessments and metabolic profiling in infants. Our specific aims are: Aim 1: Determine if biological stress during pregnancy predicts infant adiposity, distribution, and metabolic function using state-of-the-art MR imaging at birth and 5–6 months. Aim 2: Test whether MSCs from high-stress exposed infants exhibit greater cellular vulnerability under in vitro adi- pogenic challenge conditions. Stress exposure will be comprehensively quantified using ex vivo glucocorticoid-cytokine stimulation, diurnal sali- vary cortisol sampling, and maternal blood assays during early and late pregnancy. These data will be synthesized into a composite (PCA) biological stress exposure score. We hypothesize that dynamic, functionally derived measures of maternal stress will better predict infant abdominal adiposity and metabolic function than static bi- omarkers, and that stem cells from high-stress-exposed infants will exhibit greater vulnerability—reflected by in- creased lipid accumulation and hypertrophy—especially under in vitro challenge conditions. This integrated ap- proach will illuminate mechanisms of biological embedding and identify novel markers of metabolic risk. Findings will advance precision health by enabling targeted early-life interventions. This project will also establish a scalable human newborn stem cell biobank for future studies of stress-related disease pathways.