Mechanisms and Experimental Therapy of Perinatal Cerebral Hemorrhage

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Germinal matrix-intraventricular hemorrhage (GMH-IVH) is a grave but common neurological complication of prematurity, affecting 12,000 infants each year in the USA alone. While the majority of GMH-IVH occurs in the first few days after birth, postnatal intervention of this disorder is much less successful than prenatal prevention with glucocorticoids. One obstacle to this unmet clinical need has been the lack of spontaneous GMH-IVH models (as opposed to deliberate rupture of cerebral blood vessels or injection of blood into the ventricles), making it difficult to investigate the mechanisms and design strategies to prevent hemorrhage in neonates. To overcome this limitation, we have developed a transgenic mouse model of GMH-IVH by over-expressing vascular endothelial growth factor (VEGF) in the embryonic cortical germinal zone to simulate the immature vascular network in human fetuses. This animal model not only recapitulates clinical presentations of GMH- IVH-ventriculomegaly, but also responds highly favorably to prenatal glucocorticoids as in human neonates. Based on these and additional results, we hypothesize that hypoxia, ETS1 (a transcriptional factor in vascular inflammation), matrix metalloproteinases (MMPs), and angiostatin (a MMP-dependent, plasminogen-derived angiogenesis inhibitor) form a vicious cycle underlying GMH-IVH, which is intercepted by glucocorticoids at multiple junctures. Accordingly, MMPs or ETS1 are promising therapeutic targets to prevent GMH-IVH. We will test this hypothesis in two specific aims. Aim 1 focuses on the mechanisms of VEGF/hypoxia-induced perinatal cerebral hemorrhage. Aim 2 investigates pre- and post-natal prevention by comparing the efficacy of experimental therapies with the clinical medicine in each condition. Positive outcomes will provide new insights into the mechanisms of perinatal cerebral hemorrhage and suggest novel prophylactic strategies in neonates.