Altered postnatal microglial function following fetal inflammation and its effect on long-term neurodevelopment of neonatal mice

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ABSTRACT: Maternal chorioamnionitis, the most common cause of birth <28 weeks gestation, initiates a severe, immune reaction in the fetus known as the “Fetal Inflammatory Response Syndrome” (FIRS). A major consequence for preterm infants with FIRS is a much higher risk of long-term neurodevelopmental disability compared to preterm infants without FIRS. Brain injury likely occurs due to FIRS-induced prenatal activation of microglia, the resident immune cell of the central nervous system. Activated microglia contribute to brain injury for at least two important reasons: 1) Acute prenatal functional changes injure brain cells and divert microglia from developmental tasks and 2) Altered postnatal function causes abnormal microglial response to postnatal inflammatory events. The central hypothesis of this proposal is that therapeutic strategies targeting FIRS- induced mechanisms of prenatal microglial activation or postnatal inflammatory responses will prevent or resolve microglial functional abnormalities and improve neurodevelopmental outcomes. The aims of the study are: 1) to elucidate specific FIRS-induced mechanisms of microglial activation utilizing genetic inhibition and timed ex vivo therapeutic intervention approaches and 2) to test whether inhibition of prenatal microglial activation or in vivo postnatal microglial responses will normalize microglial function and prevent abnormal long-term neurodevelopment. The aims will be evaluated by using a murine model of FIRS and postnatal study of microglial function and long-term neurodevelopmental outcomes. The knowledge gained is anticipated to lead to the development of therapeutics for preterm infants affected by FIRS and to be broadly applicable to other neonatal brain injuries, including hypoxic-ischemic encephalopathy and stroke. The research and career development plans proposed will jointly facilitate the pursuit of the candidate’s long-term goals: 1) to become an independently-funded laboratory-based investigator in the fields of neonatal neuroimmunology and neurodevelopment, 2) to translate animal model findings to neonatal clinical studies, 3) to disseminate research findings nationally/internationally in order to make an impact on neonatal practice, and 4) to be a faculty mentor to students and trainees at all levels. The long-term goals will be achieved with the aid of structured mentoring and learning in the laboratory and classroom that will address immediate goals: to improve research and presentation skills, immunology and neuroscience knowledge, grantsmanship, and student mentoring. The candidate’s co-mentors were chosen to maximize their strengths related to the research project and career development plan. Dr. James Lokensgard is a neuroinflammation expert whose scientific techniques and studies of microglia match with the aims of this proposal. Dr. Michael Georgieff is an expert in neurodevelopment and preclinical models to assess early life effects on the brain. Collectively, the University of Minnesota’s commitment to the candidate through both the Academic Health Center and the Department of Pediatrics ensures the successful completion of the proposed studies.