Intracranial pressure-mediated diffuse pathologies following traumatic brain injury

项目摘要 创伤性脑损伤(TBI)是一个严重的医疗保健问题，具有惊人的个人和社会成本。 继发性颅内压升高是导致颅脑损伤加重的主要因素 人类人口中的发病率。然而，除了众所周知的高颅内压和 由于CPP降低而导致的血肿/挫伤扩张和/或随之而来的全脑缺血，几乎没有 目前已知的是由肝内胆汁淤积物介导的弥漫病变。这种知识的缺乏通过以下几个方面突显出来 目前的治疗方法在克服易产生负面结果的倾向方面的有限成功 与颅脑损伤后颅内压升高相关。这些问题引发了关于临床疗效的激烈辩论。 这种基于ICP/CPP的治疗策略，同时也对目前的 以20 mm Hg作为脑外伤后颅内压升高的治疗干预靶点。因此，长期目标是 本研究旨在探讨颅脑损伤后颅内压介导的弥漫性病理改变。最近发现，亚- 持续脑外伤和手动升高的颅内压的动物的急性神经细胞膜破裂加剧， CPP低，无脑缺血。此外，还有人建议这种病理情况会持续几天 到损伤后数周，可能通过组织蛋白酶-B介导的途径，并与颅内压介导的 慢性行为病态。根据这些发现，当前项目的目标是1)阐明 颅脑损伤后亚急性皮质神经元膜穿孔的病理进展及机制 组织蛋白酶-B介导的分子机制在本病中的作用，2)研究 弥漫性脑损伤后继发性颅内压升高对神经元病理和行为障碍的影响 确定是否有针对抑制组织蛋白酶-B途径或诱导 在颅内压升高的情况下，再次封闭膜可以减轻加重的病理和发病率。这些 AIMS将使用一种新的弥漫性脑损伤后颅内压升高的大鼠模型来解决， 允许识别和分离亚急性多孔性的荧光示踪剂输注范例 神经元。这一动物模型将与显微镜、分子和行为评估相结合，以 评估颅内压介导的弥漫性神经元病理及其与脑外伤后发病率的关系。加在一起，这些 预计研究将极大地促进对继发性脑脊髓炎病理机制的理解。 颅脑损伤后颅内压升高，并可直接转化为加强临床实践的治疗 颅脑损伤患者颅内压升高的可能性。

Project Summary Traumatic brain injury (TBI) is a serious health care problem with staggering individual and societal costs. Secondary elevation of intracranial pressure (ICP) is a major contributing factor in exacerbated TBI-initiated morbidity in the human population. However, apart from the well-known relationship between high ICP and hematoma/contusion expansion and/or ensuing global ischemia due to reduced CPP, virtually nothing is known regarding the diffuse pathologies mediated by ICP. This lack of knowledge is highlighted by the limited success of current therapies in overcoming the predisposition for negative outcomes associated with elevated ICP post TBI. These issues have sparked intense debate over the clinical efficacy of such ICP/CPP-based treatment strategies while also calling into question the current threshold of 20mmHg as a target for therapeutic intervention for elevated ICP post-TBI. Therefore, the long-term goal of this study is to investigate ICP-mediated diffuse pathologies following TBI. Recently it was found that sub- acute neuronal membrane poration is exacerbated in animals sustaining TBI and manually elevated ICP, without attendant ischemia due to low CPP. Further there was suggestion that this pathology, extends for days to weeks following injury, potentially via a cathepsin-B-mediated pathway, and is linked to ICP-mediated chronic behavioral morbidity. In accordance with these findings the current project aims to 1) elucidate the pathological progression of TBI-induced sub-acute cortical neuronal membrane poration and the involvement of cathepsin-B-mediated molecular mechanisms in this pathology, 2) investigate the effect of secondary ICP elevation on neuronal pathology and behavioral morbidity following diffuse TBI and 3) determine if novel therapies targeting either inhibition of the cathepsin-B pathway or induction of membrane resealing could alleviate exacerbated pathology and morbidity in the face of elevated ICP. These aims will be addressed using a novel rat model of ICP elevation following diffuse TBI in concert with fluorescent tracer infusion paradigms that allow for the identification and isolation of sub-acutely porated neurons. This animal model will be paired with microscopic, molecular, and behavioral assessments to evaluate ICP-mediated diffuse neuronal pathology and its link to morbidity following TBI. Together, these studies are anticipated to greatly advance understanding of the pathologies modulated by secondary elevations of ICP following TBI and could directly translate to enhanced clinical practice for the treatment of elevated ICP in TBI patients.