Intraventricular hemorrhage (IVH), or hemorrhage into the germinal matrix (GM) tissues of the developing brain, occurs in over 45% of preterm neonates of < 1500 g handicaps in this population. The risk period is independent of GA. The newborn beagle pup provides a good model for the study of neonatal IVH. This animal has a germinal matrix similar to that of a 28 - 30 week neonate, and IVH similar to those in preterm infants may be made by clinically-relevant models. The risk period for IVH in this animal is also the first 4 postnatal days. Data in both preterm neonates and the beagle pup model suggest a rapid perinatal induction of GM microvascular maturity. GM microvascular maturation in the newborn beagle pup and the preterm infant is likely mediated by soluble factors which induce, at the molecular level, level, local vascular endothelial cell maturation. This maturation is dependent on the presence of astrocytes and is characterized in part by the increased vascular deposition of basement membrane proteins and the formation of endothelial cell tight junctions. Both functional and structural genes are induced on the transcriptional level. The overall goal of this project is to identify those genes which are responsible for the induction of GM maturation in the newborn beagle pup.
The first aim i s to perform neuropathologic studies of the developing GM microvasculature during the risk period for IVH in this model.
The second aim i s to test the hypothesis that astrocytes are necessary for modulation of angiogenesis and vessel stability in this model in vitro.
The third aim will be to perform a differential screen of cDNA libraries prepared from beagle pup GM microvascular endothelium in culture from two different stages of development - before and after maturation, as evidenced by the formation of tube-like structures in vitro. The differentially expressed clones will be characterized using sequence analysis, and we will study the spatial and temporal expression of these candidate genes using immunohistochemistry and in situ hybridization.
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