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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要脑外伤（TBI）每年影响280万人，但要求加剧意识和社区对TBI的兴趣，没有针对TBI相关的病毒的有效干预措施，特别是认知障碍。有趣的是，超过50％的TBI患者表现出皮质扩散去极化（SDS）在其住院期间。这些“脑海啸”是死亡率和受伤后发病。尽管SD经常在TBI之后发生，但SD和TBI的总影响是未知。本研究将确定SD对TBI诱导的病理的影响，从而提供关键有针对性的治疗干预指南。我们的总体假设是扩散的发生 TBI后的去极化加剧了脑病理学，并且特别破坏了海马功能。我们将通过诱导的SD在TBI的大鼠模型中通过诱导的SD进行测试，并针对三个特定目标。在目标1中，我们将研究TBI+SDS是否引起更大的损伤病理和异常神经发生。在目标2中，我们将确定SDS是否导致在海马依赖行为和癫痫中定义。在我们的探索性中 AIM 3我们将在海马齿状回细胞上进行单细胞RNA测序以鉴定细胞类型特定的分子疾病来指导未来的研究。该提案将允许Ngwenya博士学习新实验和分析技术将有助于她作为独立研究人员的发展定位她询问并回答翻译神经科学中最大的问题。