MECHANISMS OF SEIZURE-INDUCED DENDRITIC INJURY

癫痫发作引起的树突损伤的机制

基本信息

批准号：
9181456
负责人：
MICHAEL WONG
金额：
$ 33.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181456
关键词：
Actins Acute Address Affect Anatomy Animal Model Attenuated Behavioral Brain Brain Injuries Brain imaging Chronic Cognitive deficits Cytoskeleton Data Dendrites Dendritic Spines Environmental Risk Factor Enzymes Epilepsy Epileptogenesis FRAP1 gene General Population Grant High Prevalence Hippocampus (Brain)Hour Human Imaging Techniques Injury Lead Learning Learning Disabilities Measures Mediating Memory Mental Retardation Microfilaments Molecular Morbidity - disease rate Mus Neurocognitive Neurologic Neurologic Deficit Neurons Neuroprotective Agents Pathologic Pathway interactions Patients Periodicity Physiological Population Research Problem behavior Process Psychosocial Factor Public Health Regulation Research Research Proposals Role Seizures Sensory Signal Pathway Signal Transduction Site Somatosensory Cortex Somatosensory Evoked Potentials Specimen Spinal Injuries Structure Symptoms Synapses Synaptic Transmission Synaptic plasticity Testing Time Work brain dysfunction cellular imaging clinically significant depolymerization experience imaging modality imaging study improved in vivo in vivo imaging inhibitor/antagonist innovation insight kainate mortality multiphoton imaging neocortical neuron loss novel novel therapeutic intervention novel therapeutics polymerization prevent psychologic public health relevance serial imaging somatosensory synaptic function

项目摘要

DESCRIPTION (provided by applicant): Epilepsy patients often experience cognitive deficits, such as memory problems, learning disabilities, and mental retardation. Although environmental and psychosocial factors can also affect brain function, there has been increasing focus on the role of seizures themselves in damaging the brain and thus causing further neurological deficits and decline in epilepsy patients, as well as progressively worsening seizures. Seizures can potentially injure the brain by a variety of mechanisms, including the death of neurons. However, since many people with epilepsy do not have obvious structural evidence of neuronal death on brain imaging or pathological studies, "non-lethal" effects of seizures on the structure and function of synapses and dendrites, the critical sites where neurons communicate, may be equally important in causing brain dysfunction in epilepsy patients. In our previous work, our lab has utilized cutting-edge imaging techniques to directly visualize in living mice injury to dendrits caused by seizures. In this project, we propose to address the hypothesis that a specific cell signaling pathway, called the mammalian target of rapamycin (mTOR) pathway, is involved in causing seizure-induced dendritic injury. First, we will use in vivo multiphoton imaging techniques to visualize whether inhibiting the mTOR pathway can prevent seizure-induced dendritic injury. Next, we will determine whether the mTOR pathway has neuroprotective effects on dendrites by regulating other cellular pathways and molecules related to the actin cytoskeleton of dendrites. Finally, we will investigate the physiological and functional consequences of seizure-induced dendritic injury related to cortical processing of sensory information in mice and test the ability of mTOR inhibitors to preserve normal function. This project should lead to important insights into the detrimental effects of seizures on dendrites and may ultimately lead to novel therapeutic approaches for preventing cognitive deficits and other neurological consequences of epilepsy.

描述（由申请人提供）：癫痫患者经常遇到认知缺陷，例如记忆问题，学习障碍和智力低下。尽管环境和社会心理因素也会影响大脑功能，但是越来越关注癫痫发作本身在损害大脑中的作用，从而导致进一步的神经缺陷和癫痫患者的下降，以及逐渐恶化的癫痫发作。癫痫发作可能会通过多种机制（包括神经元死亡）损害大脑。但是，由于许多癫痫病的人没有明显的结构证据表明神经元死亡对脑成像或病理研究，因此癫痫发作对突触和树突的结构和功能的“非致命”作用，神经元传播的关键部位在癫痫患者中引起脑功能障碍同样重要。在我们以前的工作中，我们的实验室利用了尖端的成像技术直接在活小鼠损伤中可视化对癫痫发作引起的树枝状损伤。在这个项目中，我们提出了以下假设：雷帕霉素（MTOR）途径的特定细胞信号通路（称为哺乳动物靶标）参与导致癫痫发作诱导的树突状损伤。首先，我们将使用体内多光子成像技术可视化抑制MTOR途径是否可以防止癫痫发作诱导的树突损伤。接下来，我们将通过调节与树突的肌动蛋白细胞骨架有关的其他细胞途径和分子来确定MTOR途径是否对树突具有神经保护作用。最后，我们将研究与小鼠感觉信息的皮质处理有关的癫痫发作诱导的树突状损伤的生理和功能后果，并测试MTOR抑制剂保留正常功能的能力。该项目应导致对癫痫发作对树突的有害影响的重要见解和最终可能导致新的治疗方法，以预防癫痫的认知缺陷和其他神经系统后果。