Intracranial pressure-mediated diffuse pathologies following traumatic brain injury

创伤性脑损伤后颅内压介导的弥漫性病变

基本信息

批准号：
10062517
负责人：
Audrey D Lafrenaye
金额：
$ 33.36万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062517
关键词：
Acute Address Animal Model Animals Behavior assessment Behavioral Blood flow Brain Injuries Brain Pathology Cathepsins B Cells Cellular Membrane Cerebral perfusion pressure Cessation of life Chronic Clinical Clinical Management Complex Contusions Diffuse Event Fluorescence-Activated Cell Sorting Goals Healthcare Hematoma Histologic Human Hypersensitivity Immunohistochemistry Individual Infusion procedures Injury Intracranial Hypertension Intracranial Pressure Ischemia Knowledge Lead Link Lysosomes Manuals Mediating Membrane Microscopic Modeling Molecular Morbidity - disease rate Neurons Outcome Pathologic Pathology Pathway interactions Patient Care Patients Poloxamer 188 Population Predisposition Protocols documentation Rattus Role Sensory Structure Suggestion Therapeutic Therapeutic Intervention Time Tracer Translating Traumatic Brain Injury Western Blotting attenuation base carboxypeptidase C clinical care clinical efficacy clinical practice efficacy evaluation experimental study hypoperfusion intracranial hematoma new therapeutic target novel repaired societal costs success targeted treatment treatment strategy virtual

项目摘要

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.

项目概要创伤性脑损伤 (TBI) 是一个严重的医疗保健问题，造成的个人和社会成本令人震惊。颅内压 (ICP) 继发性升高是 TBI 加重的一个主要因素人群中的发病率。然而，除了众所周知的高 ICP 与由于 CPP 减少而导致血肿/挫伤扩大和/或随后发生的全身缺血，几乎没有什么关于ICP介导的弥漫性病理学是已知的。这种知识的缺乏突出表现在目前的疗法在克服负面结果倾向方面取得的成功有限与 TBI 后 ICP 升高有关。这些问题引发了临床疗效的激烈争论这种基于 ICP/CPP 的治疗策略的研究，同时也对当前的阈值提出了质疑 20mmHg 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调查 TBI 后 ICP 介导的弥漫性病理。最近发现，亚在持续 TBI 和手动升高 ICP 的动物中，急性神经元膜穿孔加剧，没有因低 CPP 引起的缺血。此外，有人建议这种病理状态会持续数天损伤后数周，可能通过组织蛋白酶 B 介导的途径，并且与 ICP 介导的途径相关慢性行为病态。根据这些发现，当前项目的目标是 1) 阐明 TBI诱导的亚急性皮质神经元膜穿孔的病理进展及组织蛋白酶 B 介导的分子机制参与该病理学，2) 研究弥漫性 TBI 后神经元病理学和行为发病率继发性 ICP 升高和 3) 确定新疗法是否针对组织蛋白酶 B 途径的抑制或诱导面对ICP升高，膜重新密封可以缓解加剧的病理学和发病率。这些目标将通过使用弥漫性 TBI 后 ICP 升高的新型大鼠模型来实现荧光示踪剂输注范例，允许识别和分离亚急性穿孔神经元。该动物模型将与微观、分子和行为评估相结合，以评估 ICP 介导的弥漫性神经元病理学及其与 TBI 后发病率的联系。在一起，这些预计研究将极大地促进对继发性调节病理学的理解 TBI 后 ICP 升高，可直接转化为加强临床治疗实践 TBI 患者 ICP 升高的影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Buprenorphine alters microglia and astrocytes acutely following diffuse traumatic brain injury.

DOI：
10.1038/s41598-021-88030-z
发表时间：
2021-04-21
期刊：
Scientific reports
影响因子：
4.6
作者：
Ryu J;Stone P;Lee S;Payne B;Gorse K;Lafrenaye A
通讯作者：
Lafrenaye A

Microglial process convergence on axonal segments in health and disease.

DOI：
10.20517/2347-8659.2019.28
发表时间：
2020
期刊：
Neuroimmunology and neuroinflammation
影响因子：
0
作者：
Benusa SD;Lafrenaye AD
通讯作者：
Lafrenaye AD

Open late: neuronal membrane disruption late in traumatic brain injury.

DOI：
10.4103/1673-5374.313029
发表时间：
2021-12
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Hernandez ML;Cho M;Lafrenaye AD
通讯作者：
Lafrenaye AD

Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats.

DOI：
10.3390/pharmaceutics14102068
发表时间：
2022-09-28
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Ryu J;Jeizan P;Ahmed S;Ehsan S;Jose J;Regan S;Gorse K;Kelliher C;Lafrenaye A
通讯作者：
Lafrenaye A