Investigating Neurological Injury Patterns in the Minipig Following Impact

项目摘要 创伤性脑损伤（TBI）仍然是一个严重的社会问题，每年发生170万起 在美国目前，还没有神经保护药物试验能够通过III期临床试验 审判先前的体内试验涉及与临床无关的损伤模型，不包括生物学 变异性，通常是小动物模型。有必要研究脑回损伤患者的撞击性脑外伤。 使用可重复的组合平移和旋转输入损伤装置的小型猪模型。的具体目标 本研究的目的是：1）确定两种撞击诱导的TBI严重程度的急性行为和病理效应 在小型猪中，2）确定哥廷根或尤卡坦小型猪是否是更合适的大型动物 使用神经病理学、成像和行为技术的撞击诱导的TBI模型，以及3） 确定性别对撞击诱导的TBI后急性行为和病理效应的影响。复杂 将使用MR成像技术和认知/行为测试来测量与损伤前相比的变化 在同一只动物内进行纵向评估，以评价两次撞击导致的可能恢复情况 严重性组织学将确定与假手术动物相比的潜在损伤。认知障碍和 磁共振成像的变化可以与潜在的损害，使非侵入性和侵入性之间的联系 测量.这些措施还可以帮助简化转化为临床工具，以改善诊断和 干预通过评价不同的小型猪种属和性别差异来解决生物学变异性， 有助于解决当前临床前模型的一些局限性。最终，开发一个标准化的 在脑回动物模型中产生临床相关影响TBI的临床前模型将更好地 衡量药物的安全性和有效性。此外，一个良好的特征化模型可以让人们了解新药 以前使用的体内模型在非现实损伤条件下错过的目标。

Project Summary Traumatic brain injury (TBI) continues to be a serious problem in society with 1.7 million occurrences annually in the United States. Currently there have been no neuroprotective drug trials to survive past Phase III clinical trials. Previous in vivo testing, involves injury models that are not clinically-relevant, do not include biological variability and are typically small animal models. There is a need to study impact-TBI in a gyrencephalic minipig model using a repeatable combined translation and rotation-input injury device. The specific aims of this study are to: 1) Determine the acute behavioral and pathologic effects of two impact-induced TBI severities in minipigs, 2) Determine whether the Göttingen or the Yucatan minipig is the more appropriate large animal model for impact-induced TBI using neuropathological, imaging, and behavioral techniques and to 3) Determine sex influences on acute behavioral and pathologic effects following impact-induced TBI. Complex MR imaging techniques and cognitive/behavioral tests will be used to measure changes compared to pre-injury assessments and longitudinally within the same animal to evaluate possible recovery caused by two impact severities. Histology will define the underlying damage compared to sham animals. Cognitive impairments and MR imaging changes can be related to underlying damage to make a link between noninvasive and invasive measurements. These measures can also help ease translation to clinical tools to improve diagnosis and intervention. Addressing biological variability by evaluating different minipig species and sex differences will help address some of the limitations in current preclinical models. Ultimately, developing a standardized preclinical model that produces clinically-relevant impact TBI in a gyrencephalic animal model will better measure drug safety and efficacy. In addition, a well-characterized model can give insight into new drug targets that were missed by previously used in-vivo models with non-realistic injury conditions.