Investigating Neurological Injury Patterns in the Minipig Following Impact

项目摘要 颅脑损伤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性药物试验可以存活到第三临床阶段。 审判。以前的活体测试，涉及与临床无关的损伤模型，不包括生物学 可变性和典型的小动物模型。有必要研究脑回脑损伤的冲击性脑损伤 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)确定两种严重颅脑损伤的急性行为和病理效应 在小型猪中，2)确定哥廷根小型猪和尤卡坦小型猪中哪个是更合适的大型动物 使用神经病理、成像和行为技术的冲击性脑损伤模型和3) 确定性别对冲击性脑损伤后急性行为和病理效应的影响。复合体 磁共振成像技术和认知/行为测试将被用来测量与受伤前相比的变化 评估和纵向评估同一动物体内可能造成的两种影响恢复 严肃性。与假动物相比，组织学将确定潜在的损害。认知障碍和 磁共振成像的改变可能与潜在的损害有关，从而在非侵入性和侵入性之间建立联系 测量。这些措施还有助于简化向临床工具的转换，以改善诊断和 干预。通过评估不同的小型猪物种和性别差异来解决生物多样性问题 帮助解决当前临床前模型中的一些限制。最终，开发一个标准化的 在轮脑动物模型中产生临床相关影响脑外伤的临床前模型将更好 衡量药物的安全性和有效性。此外，一个具有良好特征的模型可以提供对新药的洞察。 以前使用的具有非真实损伤条件的体内模型遗漏的靶点。

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.