Microarray gene-expression analysis holds great promise to increase our molecular understanding of disease states with comprehensive coverage at the system level. Although previous studies have partially characterized the genomic response to cerebral hypoxia/ischemia and traumatic brain injury (TBI) in the adult, high-quality, microarray datasets with comprehensive transcriptome coverage in the neonate are non- existent (with one exception which is not publicly accessible). The goal of this R03 proposal is to generate and analyze comprehensive datasets of the genomic response of the diseased (injured) central nervous system using the newest Affymetrix GeneChips (> 30,000 transcripts). These datasets will be made publicly accessible for widespread dissemination through the Gene Expression Omnibus of the National Center for Biotechnology Information and the Microarray Consortium of the National Institute of Neurological Disorders and Stroke. Well-designed neonatal models of in vitro and in vivo TBI and cerebral hypoxia/ischemia will be employed. Our overriding hypothesis is that changes in gene expression, leading to altered protein expression (in the absence of confounding translational regulation), significantly contribute to delayed degeneration and cell death after TBI and cerebral hypoxia/ischemia and that the similarities between the two diseases will highlight the most critical transcriptome pathways for future, therapeutic manipulation. The concomitant generation of transcriptome datasets from both in vivo and in vitro models will allow for the direct comparison of the brain's intrinsic response to injury and its response as modified by systemic factors. The intention is that these datasets will be mined (by us and others) to create a new understanding of the temporal complexity of the biological response to CNS insults which will lead to the rational development of timed-intervention, poly-pharmaceutical strategies treating different pathways. Annual costs associated with TBI are in excess of $55 billion annually with a high incidence in the 0-4 year old population. Neonatal hypoxia/ischemia is the single most important cause of acute mortality and chronic disability in newborns with an incidence as high as 20 per 1000 births. Given the lack of current treatment options available for both condition and their enormous impact on human health, a better understanding of the cellular mechanisms leading to post-traumatic and post-hypoxic/ischemic cell death is paramount. ? ? ?
