DESCRIPTION (provided by applicant): The overarching aim of this proposal is to ensure continuation of the Neonatal and Pediatric Pharmacology Research Unit (PPRU) at the Children's Hospital of Michigan and Wayne State University (WSU) The WSU PPRU has conducted more than 40 multicenter and single site trials and has led the evaluation of drugs such as the multicenter tiral on the new formulation of intravenous ibuprofen for early closure of patent ductus artriousus in the preterm newborn. WSU PPRU ranked among the top 6 sites for subject enrollment. In addition, studies on aberrant development of serotonin biosynthesis in autistic children using PET scanning and identification of the phenotypic variants of serotonin metabolism have led to the ongoing evaluation of buspirone in drug therapy of autism. The demonstration of the role of NFKb in the gene expression of inflammatory mediators including the cyclo-oxygenases identified a target focus for drug intervention. The specific aims include: 1) the conduct of studies to generate requisite data on bioavailability, formulations, drug metabolism, pharmacokinetics, pharmacodynamics, safety, and effectiveness of new molecular entities and drugs currently used and are potentially used in the unborn fetus, newborn and children. 2) To determine the ontogeny of GABA receptors and to develop innovative pharmacotherapies of neonatal and childhood diseases such as neonatal apnea, neonatal hypoxic-ischemic encephalopathy and autism 3) To apply nanotechnology and use of dendrimers in targeted drug delivery and to develop novel formulations to modulate drug transfer across the blood brain barrier during development 4) to determine the validity of non-invasive cry analyses technique as surrogate pharmacodynamic measure in neonatal pain and non-verbal children 5) to develop novel drug therapies for fetuses with intrauterine growth retardation. 6)To determine the role of B2AR gene polymorphism in beta adrenergic response in asthmatic children and to provide a clinical milieu for the application of pharmacogenomics and proteomic technology leading to individualized pediatric pharmacotherapy and 7) to provide educational and training programs in pediatric pharmacology. Taken collectively, these initiatives will advance rational, safe, effective and cost beneficial drug therapies in the fetus, newborn and children.