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: 8976854
• 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/8976854
• 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; 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.

描述（由申请人提供）：