围产期脑出血的机制和实验治疗-猫眼课题宝

围产期脑出血的机制和实验治疗

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

项目状态：

已结题

起止时间：

2014-05-15 至 2019-04-30

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

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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.

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