Chronic neurodegenerative and neurophysiological sequela of closed-head TBI

闭合性头颅脑损伤的慢性神经退行性和神经生理学后遗症

• 批准号: 8398487
• 负责人: JOHN Eric DUDA
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398487
• 关键词: AD pathology; Acceleration; Acute; Affect; Afghanistan; Alzheimer like pathology; Alzheimer' s Disease; Amyloidosis; Animal Model; Animals; Automobile Driving; Blast Cell; Brain Pathology; Cerebral cortex; Chronic; Control Animal; Demyelinations; Diffuse; Diffuse Axonal Injury; Electrophysiology (science); Evaluation; Family suidae; Functional disorder; Head; Health; Hippocampus (Brain); Injury; Iraq; Lateral; Learning; Link; Liquid substance; Long-Term Effects; Measurement; Memory; Military Personnel; Modeling; Motor; Mus; Nerve Degeneration; Nervous System Physiology; Network-based; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Pathology; Percussion; Population; Problem Solving; Proteins; Research Personnel; Rodent; Role; Soldier; Sports; Structure-Activity Relationship; Synapses; System; Tauopathies; Techniques; Testing; Time; Transgenic Mice; Traumatic Brain Injury; Unconscious State; Veterans; War; Work; alpha synuclein; axonal degeneration; clinically relevant; early onset; mild traumatic brain injury; mouse model; neurobehavior; neurobehavioral; neurobehavioral test; neuroinflammation; neuropathology; neurophysiology; nigrostriatal system; public health relevance; relating to nervous system; synaptic function; synuclein, alpha (non A4 component of amyloid precursor) protein, human; therapeutic target; white matter

DESCRIPTION (provided by applicant): Military traumatic brain injury (TBI) has risen markedly in the current wars in Iraq and Afghanistan, and may occur in isolation or as a component of severe battlefield polytrauma. Recently, there have been estimates of 15-20% of warfighters (over 300,000 soldiers) having served in Iraq or Afghanistan having sustained at least mild TBI. These staggering numbers of afflicted warfighters make the chronic effects of TBI one of the most pressing issues affecting our Veterans. Accordingly, the overall objective of this proposal is to identify the mechanism(s) and progressive changes underlying the transition from acute to chronic pathology following closed-head TBI. Our central hypothesis is that a single severe or repeated mild closed-head TBI induces slowly progressive neurodegenerative changes over months to years post-insult. We believe these long-term neurodegenerative changes will be most apparent in the hippocampus, nigrostriatal system, aspects of the cerebral cortex, and diffuse white matter. Moreover, we hypothesize that a driving mechanism for these neurodegenerative changes is the gradual intra-axonal accumulation (and concomitant pre-synaptic depletion) of alpha-synuclein - an amyloidogenic protein - that eventually leads to more widespread axonal dysfunction, loss of synaptic efficacy, and neuronal degeneration. Initially, this will manifest as neurophysiological deficits affecting axonal efficacy and synaptic function, and will underlie a gradual neurobehavioral decline in learning, problem-solving, and motor function. To test these hypotheses, we have assembled a multi-faceted team of investigators with expertise in neurodegenerative pathologies, rodent and porcine models of TBI, and neural systems electrophysiology. We will use a pro-amyloidogenic transgenic mouse model of TBI and a swine model of closed-head rotational acceleration-induced TBI to mechanistically evaluate the pathophysiological progression from 1 month to 2 years post-injury. Importantly, the transgenic mouse studies (expressing human alpha-synuclein) will be used to directly compare the pathophysiology and neurodegenerative mechanisms in blast-TBI versus impact-TBI. In both mice and pigs, we will employ a comprehensive battery of tests including: (1) assessment of evolving neurodegenerative changes including diffuse axonal injury (DAI), Parkinson's-like Lewy pathology, Alzheimer's-like amyloidosis and tauopathies, synaptic loss, and neuroinflammation; (2) neurobehavior testing of learning, memory, motor, and problem solving; and (3) neurophysiological measurements using electrophysiological techniques sensitive to axonal loss/dysfunction, synaptic changes, and excitability changes. The evaluation of TBI-induced chronic neurodegeneration, neurobehavior, and neurophysiology in the same animals is a unique and powerful experimental platform to detect subtle neurological changes, investigate precipitating pathophysiology, and establish specific structure-function relationships. Importantly, these will be evaluated following either a single moderate or severe injury, or following repeated mild injuries. Although there is mounting evidence for links between TBI and early onset of neurodegenerative pathologies, the mechanisms of these progressive neuropathological changes following militarily relevant single or repetitive closed-head TBI are unknown. However, establishing the pathophysiological links is critical for the long-term health and neurological function of our Veterans, and thus underscores the importance and relevance of the current proposal. PUBLIC HEALTH RELEVANCE: RELEVANCE This proposal will investigate the long-term neurological consequences of traumatic brain injury (TBI), one of the most important issues facing our Veterans. TBI is considered the "signature injury" of Iraq and Afghanistan wars, with over 300,000 warfighters having been afflicted with at least mild-bTBI. While TBI in contact sports may induce brain pathology and predispose for neurodegenerative diseases, little is known about the pathophysiological progression following militarily relevant TBI. This proposal will use controlled animal models to investigate the relationship between blast and non-blast TBI and chronic neurodegenerative changes.

描述（由申请人提供）： 在伊拉克和阿富汗目前的战争中，军事创伤性脑损伤（TBI）显着上升，可能会孤立地发生，或者是严重战场多头的组成部分。最近，估计在伊拉克或阿富汗服役的战士中有15-20％的战士至少持续了轻度TBI。这些惊人的战争战士使TBI的慢性影响成为影响我们退伍军人的最紧迫的问题之一。因此，该提案的总体目的是确定闭合TBI后从急性到慢性病理过渡的机制和进行性变化。我们的中心假设是，单个严重或反复的轻度闭合头TBI在数月到侵入后数月内会引起缓慢进行性神经退行性变化。我们认为，这些长期神经退行性变化将在海马，黑质系统，大脑皮层的各个方面和弥漫性白质中最为明显。此外，我们假设这些神经退行性变化的驱动机制是α-突触核蛋白的逐型内积累（和伴随的突触前耗竭） - 一种淀粉样蛋白 - 一种淀粉样蛋白 - 最终会导致更广泛的轴突功能障碍，更广泛的轴突功能障碍，损失的损失。和神经元变性。最初，这将表现为 影响轴突疗效和突触功能的神经生理缺陷，并将是学习，解决问题和运动功能的逐渐下降的神经行为下降。为了检验这些假设，我们组装了一个多方面的研究人员团队，在TBI的神经退行性病理学，啮齿动物和猪模型以及神经系统电生理学方面具有专业知识。我们将使用TBI的促淀粉样细胞基因小鼠模型和闭合旋转加速度诱导的TBI的猪模型，以机械学评估病理生理的进展从伤害后1个月到2年。重要的是，转基因小鼠研究（表达人α-核蛋白）将用于直接比较BLAST-TBI与Impact-TBI中的病理生理学和神经退行性机制。在小鼠和猪中，我们将采用全面的测试，包括：（1）评估不断发展的神经退行性变化，包括弥漫性轴突损伤（DAI），帕金森氏症，类似帕金森氏病的病理学，阿尔茨海默氏症的糖化症状和触状症状和触症，连dauopathies，tauopathies，antaptic损失，和神经膜化症。 ; （2）学习，记忆，运动和解决问题的神经行为测试； （3）使用对轴突损耗/功能障碍，突触变化和兴奋性变化敏感的电生理技术的神经生理测量。同一动物中TBI诱导的慢性神经退行性变性，神经行为和神经生理学的评估是一个独特而强大的实验平台，可检测细微的神经系统变化，研究沉淀的病理生理学并建立特定的结构 - 功能关系。重要的是，将在一次中度或重度伤害或反复轻度伤害之后进行评估。尽管有越来越多的证据表明TBI与神经退行性病理的早期发作之间存在联系，但这些进行性神经病理学变化的机制在军事上相关的单一或重复性闭合头TBI之后的机制尚不清楚。但是，建立病理生理联系对于我们退伍军人的长期健康和神经功能至关重要，因此强调了当前建议的重要性和相关性。 公共卫生相关性： 该建议的相关性将调查创伤性脑损伤（TBI）的长期神经系统后果，这是我们退伍军人面临的最重要问题之一。 TBI被认为是伊拉克和阿富汗战争的“签名伤害”，其中30万名战士至少遭受了轻度BTBI的困扰。尽管接触运动中的TBI可能会引起神经退行性疾病的脑病理学和易感性，但对军事相关TBI后的病理生理进展知之甚少。该建议将使用受控的 动物模型研究爆炸与非爆炸TBI与慢性神经退行性变化之间的关系。