A novel ferret model of preterm encephalopathy

一种新型雪貂早产脑病模型

• 批准号: 9111076
• 负责人: Sandra E Juul
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111076
• 关键词: Acute; Affect; Animal Model; Animals; Antibodies; Architecture; Birth; Blood Vessels; Blood specimen; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Palsy; Cerebral hemisphere hemorrhage; Chronic; Cognition; Complex; Data; Development; Disease; Electroencephalography; Encephalopathies; Endotoxins; Ensure; Event; Exposure to; Ferrets; Genetically Modified Animals; Glycerol; Goals; Gray unit of radiation dose; Growth; Growth and Development function; Health; Human; Hypoxia; Immune response; Immunohistochemistry; Infant; Infection; Inflammation; Inflammatory; Injury; Interruption; Intervention; Intracranial Hemorrhages; Learning; Life; Lipopolysaccharides; Magnetic Resonance Imaging; Measurement; Modeling; Motor; Mus; Mustela putorius furo; Neonatal; Neonatal Brain Injury; Neurodevelopmental Impairment; Neurons; Neurosciences; Oryctolagus cuniculus; Outcome; Pathologic; Pattern; Perinatal; Perinatology; Physiological; Pregnancy; Premature Infant; Preterm brain injury; Rattus; Reproduction; Risk; Rodent; Rodent Model; Sheep; Staging; Survivors; Therapeutic; Third Pregnancy Trimester; Tissues; Translating; Translations; Vaccines; behavior test; cost; cytokine; fetal; gray matter; human disease; improved; instrumentation; interest; migration; mortality; neonate; neurodevelopment; neurogenesis; neuroprotection; nonhuman primate; novel; novel therapeutics; postnatal; preclinical trial; premature; prenatal; species difference; success; tool; white matter; white matter injury

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop a novel small animal model of neonatal brain injury to describe mechanisms of preterm brain injury and neuroprotection that can translate effectively to humans. Up to 50% of infants born extremely preterm develop poor outcomes involving long-term neurodevelopmental impairments affecting cognition and learning, or motor problems such as cerebral palsy. Poor outcomes arise because the preterm brain is vulnerable both to direct injury (by events such as intracerebral hemorrhage, infection and/or hypoxia), or indirect injury due to disruption of normal development. Developing white matter is particularly vulnerable to inflammation and hypoxia during the third trimester, and white matter injury is prevalent in preterm survivors. The combination of neonatal brain injury and disruption of brain development is called encephalopathy of prematurity. Rodents are the most common species used to model neonatal brain injury. But one shortcoming of using rodents is that they have a much lower proportion of white matter when compared to humans (12.5% vs. 50% white/gray). This species difference in the proportion of white matter has limited translation of rodent neuroprotective strategies to human neonates. Neonatal ferrets (Mustela putorius furo) provide a more promising opportunity to study brain injury and development relevant to preterm humans for a number of reasons. In comparison to rodents, ferrets have a more favorable white to gray matter ratio, greater cortical gyrification and, they undergo prolonged postnatal brain development so postnatal interventions may be performed at relevant stages of brain development. On postnatal day (P) 9, ferret brain development correlates well with human brain development at 25 weeks of gestation, while P21 ferret brains correspond to term gestation in human brains. We propose to create a pathophysiologically relevant ferret model of preterm brain injury that will recreate injuries associated with encephalopathy of prematurity and enable description of the underlying neuropathologic mechanisms and discovery of translatable neuroprotective strategies. Our Specific Aims are to: 1) use the bacterial endotoxin lipopolysaccharide (LPS) to create and characterize acute and chronic inflammation in P9 ferret brain; 2) evaluate the effects of hypoxia and hypoxia-ischemia on ferret brain growth and development; and 3) identify the interaction effects of acute and chronic LPS-induced inflammation with hypoxia and hypoxia-ischemia in neonatal ferret brain. Inflammatory cytokines, magnetic resonance imaging (MRI) and immunohistochemistry (IHC) will be used to assess inflammation, injury, growth and development. We are confident that completion of these aims will produce a better understanding of the pathologic mechanisms underlying neonatal brain injury, and improve our capacity to validate new therapies for human neuroprotection.

 描述（由申请人提供）：本提案的目标是开发一种新颖的新生儿脑损伤小动物模型，以描述可有效转化为人类的早产脑损伤和神经保护机制。高达 50% 的极早产婴儿结局不佳，涉及影响认知和学习的长期神经发育障碍，或脑瘫等运动问题。不良结局的出现是因为早产儿大脑容易受到直接损伤（例如脑出血、感染和/或缺氧等事件），或因正常发育中断而受到间接损伤。在妊娠晚期，正在发育的白质特别容易受到炎症和缺氧的影响，并且白质损伤在早产儿幸存者中很常见。新生儿脑损伤和大脑发育破坏的结合被称为早产儿脑病。啮齿动物是用于模拟新生儿脑损伤的最常见物种。但使用啮齿类动物的一个缺点是，与人类相比，它们的白质比例要低得多（白色/灰色为 12.5%，白色/灰色为 50%）。白质比例的这种物种差异限制了啮齿动物神经保护策略向人类新生儿的转化。由于多种原因，新生雪貂（Mustela putorius Furo）为研究与早产儿相关的脑损伤和发育提供了更有希望的机会。与啮齿类动物相比，雪貂具有更有利的白质与灰质比例、更大的皮质回旋，并且它们出生后大脑发育时间较长，因此可以在大脑发育的相关阶段进行产后干预。出生后第 9 天 (P) 时，雪貂大脑发育与妊娠 25 周时的人类大脑发育密切相关，而 P21 雪貂大脑则对应于足月妊娠的人类大脑发育。我们建议创建一个与早产儿脑损伤病理生理学相关的雪貂模型，该模型将重现与早产儿脑病相关的损伤，并能够描述潜在的神经病理机制和发现可转化的神经保护策略。我们的具体目标是：1）使用细菌内毒素脂多糖（LPS）来创建和表征 P9 雪貂大脑中的急性和慢性炎症； 2）评价缺氧和缺氧缺血对雪貂大脑生长发育的影响； 3) 确定新生雪貂脑中急性和慢性脂多糖诱导的炎症与缺氧和缺氧缺血的相互作用。炎症细胞因子、磁共振成像 (MRI) 和免疫组织化学 (IHC) 将用于评估炎症、损伤、生长和发育。我们相信，完成这些目标将更好地了解新生儿脑损伤的病理机制，并提高我们验证人类神经保护新疗法的能力。

项目成果

Is the ferret a suitable species for studying perinatal brain injury?

• DOI: 10.1016/j.ijdevneu.2015.06.005
• 发表时间: 2015-10-01
• 期刊: INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE
• 影响因子: 1.8
• 作者: Empie, Kristen;Rangarajan, Vijayeta;Juul, Sandra E.
• 通讯作者: Juul, Sandra E.

A Ferret Model of Encephalopathy of Prematurity.

早产儿脑病的雪貂模型。

• DOI: 10.1159/000498968
• 发表时间: 2018
• 期刊: Developmental neuroscience
• 影响因子: 2.9
• 作者: Wood,Thomas;Moralejo,Daniel;Corry,Kylie;Snyder,JessicaM;Traudt,Christopher;Curtis,Chad;Nance,Elizabeth;Parikh,Pratik;Juul,SandraE
• 通讯作者: Juul,SandraE

A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury.

炎症敏感的晚期早产缺氧缺血性脑损伤的雪貂模型。

• DOI: 10.3791/60131
• 发表时间: 2019
• 期刊: Journal of visualized experiments : JoVE
• 作者: Wood,Thomas;Moralejo,Daniel;Corry,Kylie;Fisher,Cole;Snyder,JessicaM;Acuna,Vivienne;Holden-Hunt,Alair;Virk,Simar;White,Olivia;Law,Janessa;Parikh,Pratik;Juul,SandraE
• 通讯作者: Juul,SandraE