Spreading Depolarizations and Brain Dysfunction Following Traumatic Brain Injury

脑外伤后去极化的扩散和脑功能障碍

• 批准号: 10093162
• 负责人: LAURA Benjamin NGWENYA
• 金额: $ 20.2万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093162
• 关键词: Address; Affect; Animals; Area; Astrocytes; Awareness; Behavior; Brain; Brain Injuries; Brain Pathology; Cell Death; Cells; Childhood; Cognition; Cognitive deficits; Communities; Development; Electroencephalography; Epilepsy; Equilibrium; Exhibits; Frequencies; Functional disorder; Future; Generations; Glutamates; Grant; Hippocampus (Brain); Histologic; Hospitalization; Hour; Human; Immediate-Early Genes; Impaired cognition; Impairment; Injury; Intervention; Ions; Knowledge; Label; Lateral; Lead; Learning; Link; Memory; Mentors; Modeling; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Neurons; Neurotransmitters; Newborn Infant; Pathologic; Pathology; Pattern; Play; Positioning Attribute; Post-Traumatic Epilepsy; Publications; Rattus; Research; Research Personnel; Role; Seizures; Surface; TBI Patients; Techniques; Testing; Therapeutic Intervention; Traumatic Brain Injury; United States National Institutes of Health; Work; adult neurogenesis; brain dysfunction; cell type; cognitive development; cognitive recovery; cognitive task; comorbidity; dentate gyrus; effective intervention; effective therapy; experimental group; fluid percussion injury; granule cell; human old age (65+); interest; mortality; neurogenesis; newborn neuron; single-cell RNA sequencing; targeted treatment; therapy development; translational neuroscience

Project Summary Traumatic brain injury (TBI) affects 2.8 million people in the US annually, but despite the heightened awareness and community interest in TBI, there are no effective interventions for TBI associated morbidities, especially cognitive impairment. Interestingly, more than 50% of patients with TBI show cortical spreading depolarizations (SDs) during their hospitalization. These “brain tsunamis” are a predictor of mortality and morbidity after injury. Despite the fact that SDs occur often after TBI, the combined impact of SDs and TBI is unknown. The present study will determine the impact of SDs on TBI-induced pathology, providing critical guidance for targeted therapeutic intervention. Our overall hypothesis is that the occurrence of spreading depolarizations after TBI exacerbates brain pathology and is especially disruptive of hippocampal function. We will test this by inducing SDs in a rat model of TBI and addressing three specific aims. In Aim 1 we will investigate whether TBI+SDs causes greater injury pathology and aberrant neurogenesis. In Aim 2 we will determine whether SDs lead to deficits in hippocampal dependent behaviors and epilepsy. In our exploratory Aim 3 we will conduct single cell RNA sequencing on hippocampal dentate gyrus cells to identify cell-type specific molecular disturbances to guide future studies. The proposal will allow Dr. Ngwenya to learn new experimental and analytic techniques that will aid in her development as an independent researcher and position her to ask and answer the largest possible questions in translational neuroscience.

项目概要 美国每年有 280 万人受到创伤性脑损伤 (TBI) 的影响，但尽管 对 TBI 的认识和社区兴趣，对 TBI 相关发病率没有有效的干预措施， 尤其是认知障碍。有趣的是，超过 50% 的 TBI 患者表现出皮质扩散 住院期间的去极化（SD）。这些“脑海啸”是死亡率和死亡率的预测因子 受伤后发病。尽管 SD 经常在 TBI 之后发生，但 SD 和 TBI 的综合影响是 未知。本研究将确定 SD 对 TBI 诱发的病理学的影响，提供关键的 指导有针对性的治疗干预。我们的总体假设是传播的发生 TBI 后的去极化会加剧大脑病理，尤其会破坏海马功能。我们 将通过在 TBI 大鼠模型中诱导 SD 并解决三个具体目标来测试这一点。在目标 1 中，我们将 研究 TBI+SD 是否会导致更大的损伤病理学和异常的神经发生。在目标 2 中，我们将 确定 SD 是否会导致海马依赖性行为和癫痫的缺陷。在我们的探索中 目标 3 我们将对海马齿状回细胞进行单细胞 RNA 测序，以确定细胞类型 特定的分子干扰来指导未来的研究。该提案将使 Ngwenya 博士能够学到新的知识 实验和分析技术将有助于她作为独立研究员的发展 让她能够提出并回答转化神经科学中最大的问题。