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 - 心理出血（GMH-IVH）是早产的严重但常见的神经系统并发症，仅在美国就会影响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比糖皮质激素对产前预防的成功要差得多。这种未满足的临床需求的一个障碍是缺乏“自发的” GMH-IVH模型（而不是故意脑血管的故意破裂或将血液注射到心室中），因此难以研究用于预防新生儿出血的机制和设计策略。为了克服这一局限性，我们通过在胚胎皮质生发区中过度表达血管内皮生长因子（VEGF）来开发GMH-IVH的转基因小鼠模型，以模拟人胎儿中未成熟的血管网络。这种动物模型不仅概括了GMH-IVH-室性肿大的临床表现，而且像人类新生儿一样，对产前糖皮质激素的反应非常好。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）和血管毒素（Angiostatin）和Angiostatin（MMP依赖性，纤溶酶原血管生成抑制剂）形成了GMH-IVH的均匀循环，从而形成了一种均匀的循环。因此，MMP或ETS1是预防GMH-IVH的有前途的治疗靶标。我们将以两个具体的目的来检验这一假设。 AIM 1专注于VEGF/缺氧诱导的围产期脑出血的机制。 AIM 2通过将实验疗法与临床医学在每种情况下的疗效进行比较，研究了产前和产后预防。积极的结果将为围产期脑出血的机制提供新的见解，并提出新生儿中新型预防性策略。