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Delayed white matter loss in concussive head injuries and its treatment

颅脑震荡迟发性脑白质丢失及其治疗

基本信息

批准号：
10354469
负责人：
Dewan Syed Fahmeed Hyder
金额：
$ 25.53万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354469
关键词：
Action Potentials Acute Animal Model Animals Anisotropy Anxiety Axon Behavior Behavioral Biological Markers Brain Brain Concussion Brain Injuries Brain imaging Chronic Clinical Clinical Trials Clinical/Radiologic Closed head injuries Collaborations Complement Corpus Callosum Correlation Studies Craniocerebral Trauma Cyclic ADP-Ribose Data Diffusion Magnetic Resonance Imaging Evolution Fiber Functional Magnetic Resonance Imaging Future Gliosis Growth Associated Protein 43 Histologic Image Individual Injury Internal Capsule Intervention Intranasal Administration LIF gene Lead Magnetic Resonance Imaging Methods Mission Modality Modeling Monitor Multimodal Imaging Mus Myelin Natural regeneration Nerve Degeneration Nervous System Physiology Neurites Neurologic Neurologic Deficit Neurological outcome Neuronal Injury Neurons Outcome Study Patients Phase Population Procedures Process Prognosis Protocols documentation Public Health Radiology Specialty Rattus Recovery Research Resolution Resources Rest Site Study models Testing Therapeutic Time Tissues Traumatic Brain Injury Treatment outcome United States National Institutes of Health Universities Veterans Water axon injury axon regeneration axonal degeneration base blood oxygen level dependent clinically relevant cohort cytokine experimental study functional decline imaging biomarker imaging study improved in vivo imaging indexing mild traumatic brain injury multimodality myelination neocortical neonatal hypoxic-ischemic brain injury neurophysiology neurovascular neurovascular coupling novel pre-clinical preservation prevent regeneration function regenerative relating to nervous system response translation to humans white matter white matter injury

项目摘要

Abstract. Half of all traumatic brain injuries cause changes in white matter integrity. Whereas progress is being made in understanding the mechanisms that lead to acute axonal injury, there is an unmet need for therapeutics to prevent delayed neuronal injury and restore neurological function. We recently demonstrated that the acute intranasal (IN) administration of the cytokine Leukemia Inhibitory factor (LIF) reduced gliosis, preserved corpus callosal myelination, preserved neocortical volumes and improved sensorimotor behavior in a neonatal hypoxic-ischemic brain injury. Here, in a mouse closed head injury (CHI) TBI model, we show that delayed IN LIF Rx prevents sensorimotor functional decline and reduces anxiety when IN LIF Rx is initiated at 6 wks of recovery. Therefore, our overall hypothesis is that intranasal LIF Rx can decrease neurological deficits after TBI by preventing delayed white matter injury and nurturing axonal regeneration by inhibiting SARM1 activation. Unequivocally demonstrating that an intervention is slowing a degenerative process and nurturing regeneration requires monitoring over time to show that it prevents the evolution of tissue damage and stimulates regeneration. Therefore, we propose to utilize high resolution multiple modality live animal magnetic resonance imaging to determine the structural and functional changes in response to IN LIF Rx. We will complement the in vivo imaging with ex-vivo diffusion tensor imaging studies and will correlate the findings with histological and neurological functional analyses. These studies will pave the way for future clinical trials where similar radiological markers can be assessed to prevent delayed white matter injury. 1

抽象。一半的脑外伤会导致白色物质完整性的改变。尽管在以下方面取得了进展，了解导致急性轴突损伤的机制后，对治疗剂的需求仍未得到满足，预防迟发性神经元损伤，恢复神经功能。我们最近证明，急性鼻内（IN）给予细胞因子白血病抑制因子（LIF）可减少神经胶质增生，胼胝体髓鞘形成，保留新皮质体积和改善感觉运动行为，新生儿缺氧缺血性脑损伤。在这里，在小鼠闭合性头部损伤（CHI）TBI模型中，我们表明，延迟IN LIF Rx可预防感觉运动功能下降，并在开始IN LIF Rx时减少焦虑， 6周恢复期因此，我们的总体假设是，鼻内LIF Rx可以减少神经功能，通过防止迟发性白色物质损伤和通过抑制轴突再生来促进轴突再生， SARM 1激活。毫不含糊地表明干预正在减缓退化过程，培育再生需要随着时间的推移进行监测，以表明它可以防止组织损伤的发展并刺激再生因此，我们建议利用高分辨率多模态活体动物磁共振成像以确定响应于IN LIF Rx的结构和功能变化。我们将用离体扩散张量成像研究补充体内成像，并将结果与组织学和神经功能分析。这些研究将为未来的研究铺平道路。临床试验，其中可以评估类似的放射学标记物以预防迟发性白色损伤。 1