A novel ferret model of preterm encephalopathy

 描述（由申请人提供）：本提案的目标是开发一种新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儿脑损伤和神经保护机制。高达50%的极早产儿发展不良的结果，涉及影响认知和学习的长期神经发育障碍，或运动问题，如脑瘫。不良结局的出现是因为早产儿的大脑容易受到直接损伤（如脑内出血、感染和/或缺氧）或由于正常发育中断而造成的间接损伤。发育中的白色物质在妊娠晚期特别容易受到炎症和缺氧的影响，并且白色物质损伤在早产存活者中普遍存在。新生儿脑损伤和脑发育中断的结合被称为早产儿脑病。啮齿动物是最常见的用于模拟新生儿脑损伤的物种。但使用啮齿动物的一个缺点是，与人类相比，它们的白色物质比例要低得多（12.5%比50%白色/灰色）。这种白色物质比例的物种差异限制了啮齿动物神经保护策略对人类新生儿的转化。新生雪貂（Mustela putorius furo）提供了一个更有前途的机会，研究脑损伤和发育相关的早产儿的人有很多原因。与啮齿动物相比，雪貂的白色与灰质比例更有利，皮质回旋更大，并且它们的产后大脑发育时间更长，因此可以在大脑发育的相关阶段进行产后干预。在出生后第9天（P），雪貂脑发育与妊娠25周的人脑发育相关性良好，而P21雪貂脑对应于人类大脑的足月妊娠。我们建议建立一个病理生理学相关的雪貂模型早产儿脑损伤，将重建与早产儿脑病相关的损伤，并能够描述潜在的神经病理学机制和发现可翻译的神经保护策略。我们的具体目标是：1）使用细菌内毒素脂多糖（LPS）在P9雪貂脑中产生并表征急性和慢性炎症; 2）评估缺氧和缺氧缺血对雪貂脑生长和发育的影响; 3）鉴定新生雪貂脑中急性和慢性LPS诱导的炎症与缺氧和缺氧缺血的交互作用。将使用炎性细胞因子、磁共振成像（MRI）和免疫组织化学（IHC）评估炎症、损伤、生长和发育。我们相信，这些目标的完成将使我们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。

 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.