EXCEED THE SPACE PROVIDED. Infants bom very prematurely are at greatly increased risk of cerebral white matter damage (defined as presence of a cranial ultrasound echolucency), which is the best neonatal predictor of cerebral palsy and severe mental retardation, and is also associated with learning and attention disorders, and visual and auditory impairments. Advances in perinatal care have had limited success in reducing the frequency of white matter damage and its developmental consequences. This study aims to provide understanding of the molecular antecedents of white matter damage, and to lay the foundation for clinical trials designed to prevent cerebral white matter damage. To achieve these goals, we will identify and measure four sets of fetal, placenta!, and neonatal biomarkers, which, in animal and in vitro studies, have been associated with an altered risk of cerebral white matter damage: 1.initiators of the fetal inflammatory response (e.g., bacteria), 2. damage promoters (e.g., pro-inflammatory cytokines), 3. modulators of the inflammatory response (e.g., anti-inflammatory cytokines, cytokine binding proteins, cytokine receptor antagonists), and 4. cerebral white matter protectors (e.g., hormones and growth promoters). We propose to enroll 1,600 infants born before 28 weeks of gestation in a multi-center study. We will: a) identify and measure clinical characteristics and experiences of the mother and her newborn; b) identify and measure in the placenta and umbilical cord: cellular morphology, infectious organisms, and receptors for, and expression of endocrine hormones and non-endocrine growth factors and their modulators; c) measure in umbilical cord blood and multiple postnatal blood samples: cytokines, hormones, and growth and survival factors; d) from a, b and c, identify the clinical, morphologic, and biochemical characteristics that predict white matter damage as indicated by an echolucency on cranial ultrasound scan; e) maintain contact with families so that at older ages (after the termination of initial funding) neurologic examinations and neuropsychologic tests can be performed; and 0 maintain a """"""""tissue bank"""""""" of placenta, umbilical cord, and blood that will be available for analyses to be suggested by future research findings. By identifying biomarkers of exposures that influence the risk of cerebral white matter damage, we expect to develop a rational and ethical basis for the design of clinical trials to reduce the occurrence of early brain damage and later developmental disabilities in the most vulnerable newborns.
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