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：
10532800
负责人：
Dewan Syed Fahmeed Hyder
金额：
$ 20.19万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532800
关键词：
Action Potentials Acute Animal Model Animals Anisotropy Axon Behavior Behavioral Biological Markers Brain Brain Concussion Brain Injuries Brain imaging Brain region 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 Magnetic Resonance Imaging Methods Mission Modality Modeling Monitor Multimodal Imaging Mus Myelin Natural regeneration Neocortex 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 TBI Patients Testing Therapeutic Time Tissues Traumatic Brain Injury Treatment outcome United States National Institutes of Health Universities Veterans Water anxiety reduction axon injury axon regeneration axonal degeneration 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 neural neurophysiology neuroprotection neurovascular neurovascular coupling novel pre-clinical preservation prevent regeneration function regenerative response segregation translation to humans white matter white matter injury

Action Potentials Acute Animal Model Animals Anisotropy Axon Behavior Behavioral Biological Markers Brain Brain Concussion Brain Injuries Brain imaging Brain region 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 Magnetic Resonance Imaging Methods Mission Modality Modeling Monitor Multimodal Imaging Mus Myelin Natural regeneration Neocortex 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 TBI Patients Testing Therapeutic Time Tissues Traumatic Brain Injury Treatment outcome United States National Institutes of Health Universities Veterans Water anxiety reduction axon injury axon regeneration axonal degeneration 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 neural neurophysiology neuroprotection neurovascular neurovascular coupling novel pre-clinical preservation prevent regeneration function regenerative response segregation translation to humans white matter white matter injury

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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

抽象的。所有创伤性脑损伤的一半导致白质完整性的变化。而进度正在了解导致急性轴突损伤的机制，因此需要治疗疗法防止神经元损伤延迟并恢复神经功能。我们最近证明了急性鼻内（IN）施用细胞因子白血病抑制因子（LIF）降低神经胶质病，保留 callosal callosal merelination，保留的新皮质体积和改善的感觉运动行为新生儿缺氧缺血性脑损伤。在这里，在鼠标闭合头部受伤（CHI）TBI模型中，我们表明延迟LIF RX可防止感觉运动功能下降并减少LIF RX的焦虑 6周恢复。因此，我们的总体假设是鼻内LIF RX可以降低神经系统 TBI后通过防止延迟的白质损伤和通过抑制来培育轴突再生的缺陷 SARM1激活。明确表明干预措施正在减缓退化过程和培养再生需要随着时间的流逝进行监测，以表明它可以防止组织损伤的演变并刺激再生。因此，我们建议利用高分辨率多种形态活动物磁共振成像以确定对LIF RX中响应的结构和功能变化。我们将与离体扩散张量成像研究补充体内成像，并将组织学和神经功能分析的发现。这些研究将为未来铺平道路可以评估类似的放射学标记以防止延迟白质损伤的临床试验。 1