Mechanisms and Experimental Therapy of Perinatal Cerebral Hemorrhage

围产期脑出血的机制和实验治疗

基本信息

批准号：
9040269
负责人：
Chia-Yi Kuan
金额：
$ 34.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040269
关键词：
Adult Affect Aftercare Angiogenesis Inhibitors Angiostatins Animal Model Animals Birth Blood Blood Vessels Brain Brain hemorrhage Cause of Death Cerebral hemisphere hemorrhage Cerebrovascular system Clinical Clinical Medicine Complication Defect Disease Dominant-Negative Mutation ETS1 gene Embryo Environment Exhibits Fetus Genetic Transcription Glucocorticoids Goals Health Hemorrhage Human Hydrocephalus Hypoxia Indomethacin Infant Infarction Inhibition of Matrix Metalloproteinases Pathway Injection of therapeutic agent Intercept Intervention Investigational Therapies MMP9 gene Marimastat Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Mediator of activation protein Modeling Neurologic Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Outcome Peptides Perinatal Perinatal subependymal hemorrhage Pharmaceutical Preparations Plasminogen Premature Infant Prevention Preventive therapy Process Prosencephalon Risk Factors Rupture Slice Stimulus Testing Tetanus Helper Peptide Transgenic Mice Transgenic Model Vascular Endothelial Growth Factors angiogenesis base comparative efficacy design disability functional disability improved insight intraventricular hemorrhage mouse model mutant neonatal care neonatal death neonate neurodevelopment novel outcome forecast overexpression postnatal premature prenatal prevent prophylactic therapeutic target vascular inflammation

项目摘要

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.

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，仅在美国每年就有 12,000 名婴儿受到影响。虽然大多数 GMH-IVH 发生在出生后的最初几天，但这种疾病的产后干预远不如使用糖皮质激素进行产前预防成功。这一未满足的临床需求的一个障碍是缺乏“自发”GMH-IVH 模型（而不是故意破裂脑血管或将血液注入心室），使得研究机制和设计预防策略变得困难新生儿出血。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）来模拟人类胎儿中不成熟的血管网络，开发了GMH-IVH转基因小鼠模型。该动物模型不仅重现了 GMH-IVH 脑室扩大的临床表现，而且与人类新生儿一样对产前糖皮质激素有高度有利的反应。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（MMP）和血管抑制素（MMP依赖性、纤溶酶原衍生的血管生成抑制剂）形成GMH-IVH潜在的恶性循环，在多个接合点被糖皮质激素拦截。因此，MMP 或 ETS1 是预防 GMH-IVH 有希望的治疗靶点。我们将在两个具体目标中检验这一假设。目标1重点研究VEGF/缺氧诱发围产期脑出血的机制。目标 2 通过比较实验疗法与临床医学在每种情况下的功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，并提出新的新生儿预防策略。