The RFA aims to stimulate research on the development of effective technologies to assess the integrity and function of the developing brain in the human fetus and newborn. We will conduct studies in the rhesus monkey that focus on four major areas of interest cited in the RFA: 1) identification of newborns with brain dysfunction due to repetitive or chronic intrauterine central nervous system (CNS) insults; 2) influences that may lead to Sudden Infant Death Syndrome (SIDS) or cerebral palsy (CP); 3) development of a nonhuman primate animal model that will enable elucidation of cause and effect between intrauterine conditions and neonatal neurologic integrity; 4) linkage of the severity of outcome with the nature of the insult. Our underlying hypothesis is that chronic disruption of maternal biorhythms will alter the normal input to the maturing fetal nervous system and thereby adversely affect neurologic integrity. We propose two experimental paradigms and a control group. We have two Specific Aims: 1) to infuse adrenocorticotropin into the maternal circulation to disrupt normal maternal (and as a result fetal) biorhythms of glucocorticoids between 120 and 155 days gestation age (dGA). We hypothesize that this perturbation will affect fetal neurological development, especially in the hippocampus, hypothalamo-hypophyseal-adrenal axis and brainstem resulting in abnormal neonatal biorhythms; 2) to disrupt the normal patterns of contracture and contraction type myometrial activity that occur in late gestation. We hypothesize that this perturbation will adversely impact the maturing central nervous system (CNS) by producing recurrent epochs of hypoxemia as well as altering sensory input to the fetus. Maternal biorhythms have fundamental influences on fetal, and subsequent neonatal, maturation. They are an important feature of maternal lifestyle. Our proposed work brings together our extensive experience over twenty years investigating pregnancy in the rhesus monkey together with an exciting new grouping of investigators who have the techniques required to conduct the proposed neonatal studies in the Laboratory for Pregnancy and Newborn Research at the College of Veterinary Medicine, Cornell University. We propose innovative approaches such as the search for placental indicators that reflect chronic intrauterine insult. We will focus on placental corticotropin releasing hormone function. We will also use our histological experience to study the developing CNS. At no extra cost we will extensively archive neonatal tissues for other investigators. Clinical pathophysiological data bases demonstrate clearly that intrauterine insult can express itself in adverse neonatal outcome. A nonhuman primate model is required to evaluate specific mechanisms of action. Preliminary data on effects of alteration of maternal pituitary- adrenal function at this stage of pregnancy on neural development indicate that the rhesus monkey is an excellent species in which to study these issues and relate them to the human newborn. We propose studies at the molecular, cellular, organ, and whole animal level. Our proposed studies will produce information of importance in relation to autonomic and CNS development in the human fetus and neonate that will aid prevention, diagnosis and management of damaging postnatal conditions such as SIDS and CP.
|Antonow-Schlorke, Iwa; Schwab, Matthias; Li, Cun et al. (2003) Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain. J Physiol 547:117-23|
|Mirmiran, M; Bernardo, L; Jenkins, S L et al. (2001) Growth, neurobehavioral and circadian rhythm development in newborn baboons. Pediatr Res 49:673-7|