Mechanisms and Experimental Therapy of Perinatal Cerebral Hemorrhage

描述（由申请人提供）：生发基质-脑室内出血（GMH-IVH）是一种严重但常见的早产儿神经系统并发症，仅在美国每年就影响12,000名婴儿。虽然大多数GMH-IVH发生在出生后的头几天，但这种疾病的产后干预远不如产前用糖皮质激素预防成功。这一未被满足的临床需求的一个障碍是缺乏“自发”的GMH-IVH模型（与故意破裂脑血管或向脑室注射血液相反），这使得研究预防新生儿出血的机制和设计策略变得困难。为了克服这一限制，我们通过在胚胎皮质生发区过度表达血管内皮生长因子（VEGF），建立了转基因小鼠GMH-IVH模型，以模拟人类胎儿的未成熟血管网络。该动物模型不仅概括了GMH- ivh -心室肿大的临床表现，而且对产前糖皮质激素的反应也与人类新生儿一样良好。基于这些和其他结果，我们假设缺氧，ETS1（血管炎症的转录因子），基质金属蛋白酶（MMPs）和血管抑制素（mmp依赖的，源自纤维溶酶原的血管生成抑制剂）形成GMH-IVH的恶性循环，在多个节点被糖皮质激素拦截。因此，MMPs或ETS1有望成为预防GMH-IVH的治疗靶点。我们将在两个具体目标中检验这一假设。目的1关注VEGF/缺氧诱导围产期脑出血的机制。目的2通过比较实验疗法和临床药物在每种情况下的疗效来研究产前和产后预防。积极的结果将为围产期脑出血的机制提供新的见解，并为新生儿提供新的预防策略。

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.