PROJECT SUMMARY (See instructions): Preterm birth affects 1 in 10 infants born in the United States, resulting in significant morbidity and economic cost. Children who are born very preterm (VPT; gestational age<32 weeks) have increased risk for impaired neurodevelopment. VPT infants experience increased physiologic stress while their caregivers experience increased psychological distress-both are associated with impaired neurodevelopment. Epigenetic modifications are proposed as a possible mechanism linking physiologic stress and neurodevelopment in VPT infants. The main objective of the proposed research is to identify the mechanisms by which neonatal physiologic stress induces epigenetic modifications that contribute to impaired neurodevelopment, as well as how caregiver distress moderates the relationship between longitudinal neonatal physiologic stress and neurodevelopmental outcomes. Specifically, the proposed research aims to (1) create and validate novel indices of neonatal physiologic stress in VPT infants; (2) identify the effects of neonatal physiologic stress on epigenetic modifications and later neurodevelopment in VPT infants; and (3) determine the effects of caregiver distress on neurodevelopment in VPT infants. This aligns with the NICHD Strategic Plan 2020 scientific priority-to reduce the incidence of neurodevelopmental disorders by improving the understanding of their origins in the developmental process and identifying potential targets and optimal timing for intervention. During the K99 phase, the Pl's molecular genetic expertise was further developed by adding training in epigenetic analyses via intensive workshops and laboratory experiences, and the Pl's quantitative expertise was expanded to include complex longitudinal analyses. Additionally, the Pl has gained exposure and knowledge of neonatal physiology via the neonatal hemodynamics program at the University of Iowa, led by Drs. McNamara and Rios. Finally, the Pl has developed professional development skills that will be critical for success as a tenure track assistant professor and independent clinical scientist. The academic environment at the University of Iowa is well-suited for the proposed research. Faculty members with expertise in advanced quantitative methods, epigenetics, and neonatal physiology are willing to continue to provide expert mentorship to the Pl as a junior faculty member. The Division of Neonatology conducts numerous research studies on preterm birth each year and has the infrastructure, including an outstanding team of clinical research nurses and a high-risk infant follow-up clinic, to support the proposed research. The Iowa Institute of Human Genetics provides researchers with a state-of-the-art, high-throughput genetic analysis facility and supports research focused on human genetics Numerous institutional organizations provide a variety of opportunities to develop the skills necessary for success as an independent clinical scientist.