Mechanisms and Experimental Therapy of Perinatal Cerebral Hemorrhage

描述(申请人提供)：生发基质-脑室出血(GMH-IVH)是早产儿的一种严重但常见的神经系统并发症，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，但对这种疾病的出生后干预远不如糖皮质激素产前预防成功。这一未得到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将血液注入脑室相反)，使得研究机制和设计预防新生儿出血的策略变得困难。为了克服这一局限性，我们建立了一种转基因GMH-IVH小鼠模型，通过在胚胎皮质生发区过表达血管内皮生长因子(VEGF)来模拟人类胚胎的未成熟血管网络。该动物模型不仅概括了GMH-IVH-脑室肥大的临床表现，而且与人类新生儿一样，对产前糖皮质激素的反应也很好。基于这些和其他结果，我们假设缺氧、ETS1(血管炎症中的转录因子)、基质金属蛋白酶(MMPs)和血管抑素(一种依赖于MMP的、纤溶酶原衍生的血管生成抑制物)形成了GMH-IVH的恶性循环，该恶性循环在多个结合点被糖皮质激素阻断。因此，MMPs或ETS1是预防GMH-IVH的有前景的治疗靶点。我们将在两个具体目标上检验这一假设。目的1探讨血管内皮生长因子/低氧致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，探讨产前和产后预防。积极的结果将为围产期脑出血的机制提供新的见解，并建议新的新生儿预防策略。

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.