Mild TBI Alters Axonal Structure, Neuronal Electrophysiology & Vascular Function

轻度 TBI 改变轴突结构、神经元电生理学

• 批准号: 8323388
• 负责人: KIMBERLE Mae JACOBS
• 金额: $ 44.28万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323388
• 关键词: Address; Animal Model; Axon; Axonal Transport; Axotomy; Basic Science; Blood Vessels; Blood flow; Brain; Brain Injuries; Cells; Cephalic; Cerebral perfusion pressure; Cerebrum; Clinical; Companions; Complex; Confocal Microscopy; Contusions; Coupled; Cysteine Protease; Detection; Diffuse Axonal Injury; Electrophysiology (science); Evaluation; Event; Failure; Healthcare; Human; Image; Imaging Techniques; Impairment; In Vitro; Injury; Intracranial Hypertension; Intracranial Pressure; Knock-out; Label; Lead; Lesion; Link; Maps; Measurement; Measures; Microcirculation; Mitochondria; Mitochondrial Swelling; Modeling; Modification; Morbidity - disease rate; Mus; Neocortex; Neurons; Nodal; Pathogenesis; Pathology; Permeability; Physiological; Play; Population; Preparation; Public Health; Role; Site; Slice; Sports; Structure; Swelling; Synapses; Synaptic plasticity; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Translating; Traumatic Brain Injury; Vasodilation; attenuation; base; bioimaging; in vivo; injured; insight; interest; neurophysiology; patch clamp; response; therapeutic target; translational approach

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a significant healthcare problem. With severe traumatic brain injury multiple forms of brain damage interact and contribute to morbidity. In contrast, with more mild to moderate TBI, overt brain damage is uncommon with diffuse axonal injury representing the dominant form of change and playing a major role in any ensuing morbidity. While in both the basic science and clinical setting there is an increased appreciation of the pathogenesis of traumatically-induced axonal injury, many questions remain regarding the precise initiation of the traumatically-induced axonal injury, its electrophysiological correlates, and its potential therapeutic targeting. Moreover, it is unknown if any related microvascular change could influence the progression of DAI and/or if repeated insults to the injured brain can further exacerbate any observed axonal/microvascular change, an issue of great significance in the field of sporting-related injury. Given the importance of these issues and their overall relevance for achieving a better understanding of TBI and its potential therapeutic management, we will address these concepts utilizing a new model of TBI in YFP- expressing mice. Using this animal model with mild TBI, we will follow those axonal changes ongoing within the neocortex, assessing their initiation and progression through modern bioimaging approaches that allows with precision, the detection of the initiating site of axonal injury wherein we can discern its associated pathogenesis. These changes will be followed in vivo and in vitro together with parallel electrophysiological studies, employed to assess ongoing change within both these axotomized neurons as well as those neurons revealing no evidence of axotomy and remaining intact. In companion with these studies, targeted therapeutic strategies will be used, together with knock-out approaches to assess their effect upon the progression of traumatically-induced axonal change and its electrophysiological sequelae. Additionally, the overlying cerebral microcirculation related to these sites of axonal injury will be assessed to determine if mild TBI impairs their reactivity to known physiological challenges. These issues will be addressed not only in the context of mild TBI uncomplicated by secondary insult but also, they will be reevaluated in the context of repeated mild TBI to determine if the repeat injury exacerbates any observed structural or functional change. We will also explore if repeat injury precipitates an enduring cascade of microvascular abnormalities that lead to sustained vasodilation, lack of vascular responsivity, elevated intracranial pressure, and subsequent reduction of cerebral perfusion pressure. Through the conduct of the studies proposed we believe that we will provide unprecedented insight into the initiating pathogenesis of traumatically-induced axonal injury and its potential therapeutic modification. Similarly, the proposed electrophysiological studies should provide unique insight into the neurophysiological sequelae of mild TBI, revealing alterations not only in the axotomized populations but also in the related non-axotomized/intact neuronal population. Lastly, through the use of repeated injuries, we hope to provide critical insight into the pathobiology underlying the significant morbidity associated with this condition, which is a major confound of sporting-related injury. In our estimation, the studies proposed are not only descriptive but also mechanistic, therapeutic, and translational, thereby providing a relatively sophisticated platform for addressing some of the most complex issues currently confounding our understanding of mild TBI.

描述（由申请人提供）：创伤性脑损伤（TBI）仍然是一个重大的医疗保健问题。由于严重的脑损伤，多种形式的脑损伤相互作用并导致发病率。相比之下，具有更轻度至中度的TBI，明显的大脑损伤并不常见，弥散的轴突损伤代表了变化的主要形式，并且在任何随之而来的发病率中都起着重要作用。尽管在基础科学和临床环境中，人们对创伤引起的轴突损伤的发病机理有了增加的认识，但关于创伤引起的轴突损伤的精确起始，其电生理相关性及其潜在的治疗靶标仍然存在许多问题。此外，尚不清楚是否有任何相关的微血管变化会影响DAI和/或反复侮辱受伤的大脑的进展，可以进一步加剧任何观察到的轴突/微血管变化，这在与运动相关损伤领域中具有重要意义的问题。鉴于这些问题的重要性及其对更好地了解TBI及其潜在的治疗管理的重要性，我们将利用YFP表达的小鼠的新模型来解决这些概念。使用这种动物模型与轻度TBI，我们将遵循新皮层中正在进行的轴突变化，通过现代的生物成像方法评估其起始和进展，从而可以精确地检测轴突损伤的起始位点，我们可以识别其相关的病原体。这些变化将在体内和体外以及平行的电生理研究中遵循，用于评估这些轴突化神经元内的持续变化以及那些没有揭示轴突切开术和保持完整迹象的神经元。为了伴随这些研究，将使用有针对性的治疗策略，以及敲除方法，以评估它们对创伤引起的轴突变化及其电生理后遗症的影响。此外，将评估与这些轴突损伤部位相关的上覆的大脑微循环，以确定轻度TBI是否会损害其对已知生理挑战的反应性。这些问题将不仅在次要侮辱简单的轻度TBI中解决，而且还将在重复轻度TBI的背景下重新评估它们，以确定重复损伤是否加剧了任何观察到的结构或功能变化。我们还将探讨重复损伤是否会导致一系列持久的微血管异常级联反应，从而导致血管舒张，缺乏血管反应性，颅内压升高以及随后降低大脑灌注压力。通过提出的研究的进行，我们认为我们将为创伤引起的轴突损伤的发病机理提供前所未有的见解及其潜在的治疗修饰。同样，拟议的电生理研究应提供对轻度TBI神经生理后遗症的独特见解，不仅在轴测质中，而且在相关的非轴轴化/完整的神经元种群中也发生了变化。最后，通过使用反复伤害，我们希望对与这种情况相关的重要发病率的病理生物学提供重要的见解，这是与运动相关的损伤的主要混淆。在我们的估计中，提出的研究不仅是描述性的，而且是机械，治疗和翻译，从而提供了一个相对复杂的平台，以解决目前最复杂的问题，以困惑我们对轻度TBI的理解。