Intracranial pressure-mediated diffuse pathologies following traumatic brain injury

项目摘要 创伤性脑损伤（TBI）是一个严重的卫生保健问题，个人和社会成本惊人。 继发性颅内压（ICP）升高是TBI引发的急性脑梗死的主要促发因素。 人类的发病率。然而，除了众所周知的高ICP与 由于CPP降低，血肿/挫伤扩大和/或随后的全脑缺血， 关于ICP介导的弥漫性病理学是已知的。这种缺乏知识的情况突出表现在： 目前的治疗在克服负面结果的倾向方面取得的成功有限 与脑外伤后颅内压升高有关这些问题引发了对临床疗效的激烈争论 这种基于ICP/CPP的治疗策略，同时也对目前的 20 mmHg作为TBI后ICP升高的治疗干预目标。因此，长期目标是 本研究旨在研究脑外伤后ICP介导的弥漫性病变。最近发现， 急性神经元膜穿孔在持续TBI和手动升高ICP的动物中加剧， 而没有由于低CPP而伴随的局部缺血。此外，有人建议，这种病理，延长了几天 至损伤后数周，可能通过组织蛋白酶B介导的途径，并与ICP介导的 慢性行为发病率。根据这些发现，本项目旨在1）阐明 TBI诱导的亚急性皮层神经元膜穿孔的病理进展和 组织蛋白酶B介导的分子机制参与这种病理学，2）研究 弥漫性TBI后继发性ICP升高对神经元病理学和行为发病率的影响，以及3） 确定靶向抑制组织蛋白酶-B通路或诱导 膜再密封可以减轻在面对升高的ICP时恶化的病理和发病率。这些 将使用弥漫性TBI后ICP升高的新型大鼠模型， 荧光示踪剂输注范例，其允许鉴定和分离亚急性穿孔的 神经元该动物模型将与显微镜、分子和行为评估配对， 评估ICP介导的弥漫性神经元病理学及其与TBI后发病率的关系。所有这些 研究预计将大大促进对继发性脑缺血所调节的病理学的理解， TBI后ICP升高，并可直接转化为治疗的临床实践增强 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.